Methods for topical delivery of prostaglandins to subcutaneous fat

ABSTRACT

Described herein are compositions comprising a prostaglandin FP receptor agonist (PFPRA) compound and a fatty acid ester (e.g., isopropyl myristate), optionally comprising an ointment base such as a hydrocarbon base (e.g., petroleum jelly) and/or an organic alcohol (e.g., propylene glycol), that, when topically applied to the skin, locally delivers a therapeutically effective amount of the PFPRA compound to subcutaneous fat under the skin, and methods of preparation. The therapeutic effect is, for example, reduction of the subcutaneous fat under the skin. Further provided are methods of reducing body fat in a subject comprising topically administering the composition to the subject.

RELATED APPLICATIONS

This application is a continuation of and claims priority under 35U.S.C. §120 to U.S. application, U.S. Ser. No. 14/575,873, filed Dec.18, 2014, which claims priority under 35 U.S.C. §365(c) to and is acontinuation of international PCT Application, PCT/US2014/037512, filedMay 9, 2014, which claims priority under 35 U.S.C. §119(e) to U.S.provisional patent application, U.S. Ser. No. 61/822,139, filed May 10,2013, each of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to methods and compositions for topicallydelivering a therapeutically effective amount of a prostaglandin FPreceptor agonist (a PFPRA compound) to adipose tissue under the skin.The therapeutic effect is, for example, reduction of excess fat underthe skin, for example, the skin of the face, eyelids, neck, chin,submental region, limbs, breast, abdomen, hips, etc. More specifically,the invention relates to new compositions comprising a PFPRA compoundand a fatty acid ester (e.g., isopropyl myristate), optionally furthercomprising an ointment base such as a hydrocarbon base (e.g., petroleumjelly), and/or optionally further comprising an organic alcohol (e.g.,propylene glycol). The invention further relates to methods comprisingapplying the aforementioned composition(s) to the skin. The inventionfurther relates to processes for manufacturing the aforementionedcomposition(s).

Experimentally, in comparison to a wide array of other compositionstested, the compositions disclosed herein demonstrate exceptional andsurprising efficiency in delivering certain PFPRA compounds across skinin vitro, in delivering a therapeutically effective amount to fat belowthe skin in vivo, and/or in reducing subcutaneous fat in vivo. Intheory, this surprising efficiency may owe to the similar structure andpolarity between the PFPRA compound (e.g., latanoprost) and the fattyacid ester (e.g., isopropyl myristate), as described herein. Thecompositions are non-irritating, well-tolerated, and aestheticallypleasing. As a further advantage, they are considered suitable forapplication to the face, the eyelid, and/or periorbital skin.Furthermore, the compositions are stable and can be readilymanufactured, where necessary in sterile form.

BACKGROUND OF THE INVENTION

Excess body fat is an important cause of human disease, disability, andcosmetic disturbance. For many people excess body fat is also a sourceof psychosocial distress and reduced self-esteem.

Excess body fat may be diffuse or concentrated on particular portion(s)of the body. Of particular importance is excess body fat of the face,for example, of the eyelids, chin, or jowls. Other important sites ofexcess body fat can include, for example, the arms, abdomen, buttocks,hips, chest, thighs, and neck. Excess body fat can also involveexcessive breast tissue on a woman or on a man, i.e., gynecomastia.Excess body fat can be located within or near the eyelids, and topicaltreatment of such fat requires a composition that is safe forapplication near the eyes, i.e. an ophthalmic and/or ophthalmicallycompatible formulation. Local accumulations of body fat may result fromconstitutional factors, disease, hormonal status, or as side effects ofmedication or other substances. Even in the absence of disease, cosmeticconsiderations apply to individuals who nevertheless perceive an excessof fat and wish to have it corrected. For example, excess submental fat,commonly known as “double chin,” is not considered a disease; however,people with excess submental fat often appear less attractive and lessyouthful, and can have lower self-esteem as a result. Likewise, anindividual may have excess subcutaneous fat on the anterior abdomen,excess subcutaneous fat on the oblique abdomen, e.g. above the iliaccrests (“love handles”), excess chest fat, excess breast fat, excessbuttocks fat, excess hip fat, excess thigh fat, excess leg fat, excessupper arm fat, excess check fat, excess neck fat, etc.

A number of medical conditions are considered to be causes of excessbody fat. Examples include drug-induced obesity, hypothyroidism,pseudohypoparathyroidism, hypothalamic obesity, polycystic ovariandisease, depression, binge eating, Prader-Willi syndrome, Bardet-Biedlsyndrome, Cohen syndrome, Down syndrome, Turner syndrome, growth hormonedeficiency, growth hormone resistance, and leptin deficiency orresistance. Disfiguring excess regional fat deposits, for example excessdorsocervical fat, may be found in conditions such as HIV lipodystrophy,Cushing syndrome and pseudo-Cushing syndrome (i.e., characteristicsyndrome of excess body fat and other findings due to excessiveendogenous or exogenous corticosteroid levels), other acquiredlipodystrophies, familial lipodystrophies, lipoma, lipomatosis, andMadelung disease.

Medications known to cause excess body fat include cortisol and analogs,other corticosteroids, megace, sulfonylureas, antiretrovirals, tricyclicantidepressants, monoamine oxidase inhibitors, selective serotoninreuptake inhibitors, oral contraceptives, insulin, risperidone,clozapine, and thiazolidinediones.

Changes in hormonal status, including physiologic changes such aspregnancy or menopause, may result in excess body fat in a subject.Smoking cessation commonly leads to weight gain and excess body fat.Trauma may favor the accumulation of excess body fat by virtue ofimmobility or disuse of an extremity. Similar problems may affect asubject who is immobilized, for example due to an injury. Some tumors,for example lipomas and liposarcomas, are characterized by localcollections of fat cells. Lipomatosis is any condition characterized bythe formation of multiple lipomas on the body, e.g., familial multiplelipomatosis, adiposis dolorosis (Dercum's disease), pelvic lipomatosis,etc.

Even in the absence of underlying pathology, an individual may havecosmetic concerns about local or diffuse deposits of body fat. These canusually be attributed to constitutional or hereditary factors,developmental history, age, gender, diet, alcohol use, or othercomponents of lifestyle. Individuals in such circumstances commonly wishto reduce the amount of fat on the face, eyelids, chin, arms, neck,abdomen, chest, breast, buttocks, hips, thighs, and/or legs. In somecases a local excess of fat can be due to fat prolapse, displacement,and/or migration, as in age-related orbital fat prolapse or descent ofmalar fat pads. Grave's ophthalmopathy (thyroid-related eye disease) isa condition that can be treated by reducing the volume of orbital fat.

A number of methods have been developed to reduce or remove excess bodyfat. It is helpful to classify these methods as extractive, metabolic,or adipolytic. Extractive methods, such as lipoplasty (e.g.,liposuction) or local excision, are methods whereby fat is physicallyremoved from areas of interest. Such methods are costly and may involvescars, postsurgical deformity or regression, discomfort, infection, andother adverse reactions.

In contrast to extractive methods, metabolic methods, which includesystemic medications, nutritional supplements, devices, and exercise orother body treatment, seek to modify the subject's metabolism (e.g.,whether caloric consumption, expenditure, or both) such that the subjectincurs a net loss of fat. A disadvantage is that these methods typicallycannot be directed to a particular part of the body. Another drawback ispotential concomitant loss of water, carbohydrates, protein, vitamins,minerals, and other nutrients. Furthermore, traditional diet medicationsmay have undesired side effects, for example palpitations, tremor,insomnia, and/or irritability in a subject who uses stimulants asappetite suppressants. Despite salubrious value, the traditionalmetabolic methods of diet and exercise are not practical for everybody.

Adipolytic methods aim to cause breakdown of adipocytes and/or theirlipid contents. For example, fat deposits can be reduced by exposure tocold temperature or to deoxycholate, a solubilizer that lyses cellmembranes and results in local necrosis. Drawbacks of these methods caninclude poor discrimination between adipose and other nearby tissues,barriers to delivery that require hypodermic needles or specialequipment, and adverse effects such as necrosis, inflammation, and pain.

Compounds of the prostaglandin FP receptor agonist (PFPRA compound)class, e.g., latanoprost and tafluprost, can be administered to the skinto locally reduce adipose tissue under the skin, i.e., subcutaneous fat.See, e.g., U.S. Pat. No. 8,426,471 and U.S. Publication No.2010/0234466, incorporated herein by reference. Developing topicaldelivery of the PFPRA compound poses significant challenges, sincedelivery to subcutaneous fat comprises delivery across the stratumcorneum, epidermis, dermis, and dermal microcirculation, and into thefat below.

For example, the skin, in particular the stratum corneum, presents aformidable physical barrier to drug penetration. See, e.g., Dayan N,Delivery System Design in Topically Applied Formulations: An Overview,in Rosen M, Delivery System Handbook for Personal Care and CosmeticProducts, William Andrew, 2005, pp. 103-104. For any particular drug,the formulation must be selected empirically. The formulation must bephysically and chemically compatible with the drug.

Furthermore, provided that a formulation enables a drug to cross theskin, to reach the subcutaneous fat it must also circumvent what isknown as the “sink condition” of the dermal circulation. See, e.g.,Dayan N, Delivery System Design in Topically Applied Formulations: AnOverview, in Rosen M, Delivery System Handbook for Personal Care andCosmetic Products, William Andrew, 2005, pp. 103-104; Kao J, In VitroAssessment of Dermal Absorption, in Hobson D W, Dermal and OcularToxicology: Fundamentals and Methods, CRC Press, 1991, pp. 272-273.Because the dermis is invested by a network of capillaries with rapidblood flow, for any solute (e.g., drug) that penetrates the dermis, awide concentration gradient is created between the skin and bloodstream.Thus, there is a strong tendency for drugs that penetrate into thedermis to diffuse rapidly down this gradient into the bloodstream. Thissink phenomenon favors systemic delivery (e.g., to the bloodstream, aswith a nicotine patch), but undermines attempts at local delivery (e.g.,to subcutaneous fat, as in the present invention). No method ofreasoning or prediction is available in the art to suggest whichformulations, if any, can circumvent the sink condition. Therefore, theartisan must search for such formulations empirically, and without priorknowledge that such formulation even exists.

The formulation must also have a favorable systemic drug exposureprofile, e.g., that avoids excessive levels of drug in the bloodstream.This requirement is rendered more difficult by the sink condition.

Additionally, the formulation should deliver the active ingredient withreasonable efficiency. One measure of efficiency is the ability tominimize the concentration of active ingredient in the finished productand still maintain the desired therapeutic effect. This has implicationsfor manufacturability, cost of goods, and local safety and tolerability.Another measure of efficiency is the ability to minimize the dosefrequency and still maintain the desired therapeutic effect, which hasimplications for patient convenience and product marketability.

As well, the formulation must cause little or no skin irritation. Ifapplied to skin near the eye, e.g., the eyelid, the formulation isconsidered an ophthalmic formulation. Generally, an ophthalmicformulation must be sterile, e.g., according to Chapter <71> of the U.S.Pharmacopeia. Preferably, an ophthalmic formulation must also be free oressentially free of bacterial endotoxin, e.g. according to Chapter <85>of the U.S. Pharmacopeia, e.g., an endotoxin level of <10 EU (endotoxinunits) per gram of composition. If applied to skin near the eye, theformulation must be ophthalmically compatible, i.e, the formulation mustnot cause clinically significant eye irritation, and must not be toxicto the eye, e.g., the ocular surface, e.g. the cornea. Irritationpotential and ocular toxicity are studied empirically by standardpreclinical models, or in human trials. Although the skin or eyeirritation potential of individual inactive ingredients is generallyknown, combinations of inactive and active ingredients can causeunexpected irritation, which must be tested empirically.

Furthermore, the formulation must possess other qualities necessary tomake a topical formulation and market it to consumers: ease ofmanufacture, physical and chemical stability, and commerciallyacceptable appearance, odor, and tactile qualities.

Therefore, there is a need for new compositions for topically deliveringa PFPRA compound to adipose tissue under the skin.

SUMMARY OF THE INVENTION

It has now been discovered experimentally that certain topicalcompositions comprising a PFPRA compound (e.g., latanoprost ortafluprost) and certain fatty acid esters (e.g., isopropyl myristate)provide exceptionally efficient delivery of the compound and its activemetabolite into subcutaneous fat, and thus have particular uses andadvantages, as described herein. In theory, this efficiency may owe tothe similar structure and polarity between the PFPRA compound (e.g.,latanoprost or tafluprost) and the fatty acid ester (e.g., isopropylmyristate), as described herein.

Thus, in one aspect, provided is a composition useful in the reductionof subcutaneous fat comprising a PFPRA compound, e.g. latanoprost ortafluprost, and a fatty acid ester, e.g., isopropyl myristate. Incertain embodiments, the concentration of the PFPRA compound in thecomposition is between about 0.0001 percent to about 1 percent byweight, as a proportion of the total weight of the composition, e.g.,between about 0.05 percent and about 0.5 percent by weight, or betweenabout 0.01 percent and about 0.1 percent by weight of the finalcomposition. In some embodiments, the final concentration of the fattyacid ester (e.g., isopropyl myristate) is between about 1 percent toabout 20 percent by weight, e.g., between about 1 percent and about 10percent by weight of the composition. In certain embodiments, thecomposition further comprises an ointment base, e.g., a hydrocarbon basesuch as petroleum jelly. In some embodiments, the final concentration ofthe ointment base is between about 50 percent and about 99 percent byweight, e.g., between about 70 percent and about 99 percent by weight,of the total weight of the composition. In some embodiments, thecomposition further comprises an organic alcohol (e.g., propyleneglycol). In some embodiments, the final concentration of the organicalcohol is between about 5 percent and about 50 percent by weight, e.g.,between about 5 percent and about 20 percent by weight, of the totalweight of the composition. In some embodiments, the composition is notan emulsion. In some embodiments, the composition is immiscible inwater. In some embodiments, the composition is an ophthalmic compositionand is ophthalmically compatible. In some embodiments, the compositionis sterile.

In another aspect, provided is a method of reducing body fat in asubject, comprising topically administering a composition as describedherein to a subject in need thereof. In certain embodiments, the methodis a therapeutic method. In other embodiments, the method is a cosmeticmethod.

In another aspect, provided is a composition as described herein for usein a method of reducing body fat in a subject. In another aspect,provided is use of a composition as described herein in the manufactureof a medicament for reducing body fat in a subject.

In another aspect, provided is a composition for use in for reducing fatin a subject suffering from steatoblepharon. In another aspect, providedis a method of treating steatoblepharon in a subject, comprisingtopically administering (e.g., applying to an eyelid of the subject) acomposition as described herein to a subject in need thereof. In anotheraspect, provided is a composition as described herein for use in amethod of treating steatoblepharon in a subject. In another aspect,provided is use a composition as described herein in the manufacture ofa medicament for treating steatoblepharon in a subject.

In yet another aspect, provided is a kit comprising a composition asdescribed herein and instructions for use.

In another aspect, provided is a process for manufacturing one or moreof the inventive compositions in a sterile fashion, whereby thecomposition is sterile, endotoxin-free, and ophthalmically compatible,and therefore suitable for use on the eyelid or near the eye. Forexample, in one embodiment, provided is a process for manufacturing asterile ointment, comprising the steps of dissolving a PFPRA compound(e.g. latanoprost or tafluprost) in a fatty acid ester (e.g., isopropylmyristate) to make a solution; microfiltration of the solution to make afiltrate; and combining the filtrate with an ointment base (e.g., ahydrocarbon base such as petroleum jelly). In certain embodiments, themethod further comprises dissolving a preservative (e.g., chlorobutanol)in the fatty acid ester (e.g., isopropyl myristate).

Other objects and advantages will become apparent to those skilled inthe art from consideration of the ensuing Detailed Description,Examples, and Claims.

DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts three-dimensional molecular models of isopropyl myristateand latanoprost in energy-minimized conformations (solved in vacuo).Carbon atoms are shown in gray and oxygen atoms in red; hydrogens arenot shown. Measured end-to-end distances (between heavy atom centers)are 19.9 Å for isopropyl myristate and 17.7 Å for latanoprost.

DEFINITIONS Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Certain compounds as described herein can comprise one or moreasymmetric centers, and thus can exist in various isomeric forms, e.g.,enantiomers and/or diastereomers. The compounds provided herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer. Incertain embodiments, the compounds as described herein are enantiopurecompounds. In certain other embodiments, mixtures of stereoisomers areprovided.

Furthermore, certain compounds, as described herein may have one or moredouble bonds that can exist as either the cis or trans, or the E or Zisomer, unless otherwise indicated. The invention additionallyencompasses the compounds as individual isomers substantially free ofother isomers, and alternatively, as mixtures of various isomers, e.g.,racemic mixtures of E/Z isomers or mixtures enriched in one E/Z isomer.

The terms “enantiomerically enriched,” “enantiomerically pure” and“non-racemic,” as used interchangeably herein, refer to compositions inwhich the percent by weight of one enantiomer is greater than the amountof that one enantiomer in a control mixture of the racemic composition(e.g., greater than 1:1 by weight). For example, an enantiomericallyenriched preparation of the (S)-enantiomer, means a preparation of thecompound having greater than 50% by weight of the (S)-enantiomerrelative to the (R)-enantiomer, more preferably at least 75% by weight,and even more preferably at least 80% by weight. In some embodiments,the enrichment can be much greater than 80% by weight, providing a“substantially enantiomerically enriched,” “substantiallyenantiomerically pure” or a “substantially non-racemic” preparation,which refers to preparations of compositions which have at least 85% byweight of one enantiomer relative to other enantiomer, more preferablyat least 90% by weight, and even more preferably at least 95% by weight.In preferred embodiments, the enantiomerically enriched composition hasa higher potency with respect to therapeutic utility per unit mass thandoes the racemic mixture of that composition. Enantiomers can beisolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred enantiomerscan be prepared by asymmetric syntheses. See, for example, Jacques, etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGrawHill, N.Y., 1962); andWilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

When a range of values is listed, it is intended to encompass each valueand sub range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein, “aliphatic” refers to an alkyl, alkenyl, alkynyl, orcarbocyclyl group, as defined herein.

As used herein, alone or as part of another group, “alkyl” refers to aradical of a straight-chain or branched saturated hydrocarbon grouphaving from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). In some embodiments,an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀ alkyl”). In someembodiments, an alkyl group has 1 to 6 carbon atoms (“C₁₋₆ alkyl”). Insome embodiments, an alkyl group has 1 to 5 carbon atoms (“C₁₋₅ alkyl”).In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C₁₋₄alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms(“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1 to 2 carbonatoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl group has 1 carbonatom (“C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbonatoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groups include methyl (C₁),ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl(C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅),amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅),and n-hexyl (C₆). Unless otherwise specified, each instance of an alkylgroup is independently unsubstituted (an “unsubstituted alkyl”) orsubstituted (a “substituted alkyl”) are substituted with one or moresubstituents. In certain embodiments, the alkyl group is anunsubstituted C₁₋₆ alkyl (e.g., CH₃). In certain embodiments, the alkylgroup is a substituted C₁₋₆ alkyl.

As used herein “perhaloalkyl” or “halosubstituted alkyl” as definedherein refers to an alkyl group having from 1 to 10 carbon atoms whereinall of the hydrogen atoms are each independently replaced halogen, e.g.,selected from fluoro, bromo, chloro or iodo (“C₁₋₁₀ perhaloalkyl”). Insome embodiments, the alkyl moiety has 1 to 6 carbon atoms (“C₁₋₆perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 5 carbonatoms (“C₁₋₅ perhaloalkyl 1”). In some embodiments, the alkyl moiety has1 to 4 carbon atoms (“C₁₋₄ perhaloalkyl”). In some embodiments, thealkyl moiety has 1 to 3 carbon atoms (“C₁₋₃ perhaloalkyl”). In someembodiments, the alkyl moiety has 1 to 2 carbon atoms (“C₁₋₂perhaloalkyl”). In some embodiments, all of the hydrogen atoms are eachreplaced with fluoro. In some embodiments, all of the hydrogen atoms areeach replaced with chloro. Examples of perhaloalkyl groups include CF₃,CF₂CF₃, CF₂CF₂CF₃, CCl₃, CFCl₂, CF₂Cl and the like.

As used herein, “alkyloxy” refers to an alkyl group, as defined herein,substituted with an oxygen atom, wherein the point of attachment is theoxygen atom. In certain embodiments, the alkyl group has 1 to 6 carbonatoms (“C₁₋₆ alkyloxy”). In some embodiments, the alkyl group has 1 to 4carbon atoms (“C₁₋₄ alkyloxy”). Examples of C₁₋₄ alkyloxy groups includemethoxy (C₁), ethoxy (C₂), propoxy (C₃), isopropoxy (C₃), butoxy (C₄),tertbutoxy (C₅) and the like. Examples of C₁₋₆ alkyloxy groups includethe aforementioned C₁₋₄ alkyloxy groups as well as pentyloxy (C₅),isopentyloxy (C₅), neopentyloxy (C₅), hexyloxy (C₆) and the like. Unlessotherwise specified, each instance of the alkyl moiety of the alkyloxygroup is independently unsubstituted (an “unsubstituted alkyloxy”) orsubstituted (a “substituted alkyloxy”) with one or more substituents. Incertain embodiments, the alkyloxy group is an unsubstituted C₁₋₆alkyloxy. In certain embodiments, the alkyloxy group is a substitutedC₁₋₆ alkyloxy.

As used herein, “alkylcarboxy” refers to a group of the formulaC(═O)OR^(a) wherein R^(a) is an alkyl group as defined herein. Incertain embodiments, the alkyl of the alkylcarboxy group has 1 to 6carbon atoms (“C₁₋₆ alkylcarboxy”). In some embodiments, the alkyl ofthe alkylcarboxy group has 1 to 5 carbon atoms (“C₁₋₅ alkylcarboxy”). Insome embodiments, the alkyl of the alkylcarboxy group has 1 to 4 carbonatoms (“C₁ alkylcarboxy”). In some embodiments, the alkyl of thealkylcarboxy group has 1 to 3 carbon atoms (“C₁₋₃ alkylcarboxy”). Insome embodiments, the alkyl of the alkylcarboxy group has 1 to 2 carbonatoms (“C₁₋₂ alkylcarboxy”). Unless otherwise specified, each instanceof the alkyl of the alkylcarboxy group is independently unsubstituted(an “unsubstituted alkylcarboxy”) or substituted (a “substitutedalkylcarboxy”) with one or more substituents. In certain embodiments,the alkylcarboxy group is an unsubstituted C₁₋₆ alkylcarboxy. In certainembodiments, the alkylcarboxy group is a substituted C₁₋₆ alkylcarboxy.

As used herein, alone or as part of another group, “alkenyl” refers to aradical of a straight-chain or branched hydrocarbon group having from 2to 20 carbon atoms and one or more carbon-carbon double bonds (“C₂₋₂₀alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbonatoms (“C₂₋₁₀ alkenyl”). In some embodiments, an alkenyl group has 2 to6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl grouphas 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, analkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In someembodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”).In some embodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”).The one or more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1 Examples of C₂₋₄ alkenyl groupsinclude ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄),2-butenyl (C₄), butadienyl (C₄) and the like. Examples of C₂₋₆ alkenylgroups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆) and the like. Unlessotherwise specified, each instance of an alkenyl group is independentlyunsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is an unsubstituted C₂₋₆ alkenyl. Incertain embodiments, the alkenyl group is a substituted C₂₋₆ alkenyl.

As used herein, alone or as part of another group, “alkynyl” refers to aradical of a straight-chain or branched hydrocarbon group having from 2to 20 carbon atoms and one or more carbon-carbon triple bonds (“C₂₋₂₀alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbonatoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl group has 2 to6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In some embodiments, analkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”). In someembodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃ alkynyl”).In some embodiments, an alkynyl group has 2 carbon atom (“C₂ alkynyl”).The one or more carbon-carbon triple bonds can be internal (such as in2-butynyl) or terminal (such as in 1 Examples of C₂₋₄ alkynyl groupsinclude, without limitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl(C₃), 1-butynyl (C₄), 2-butynyl (C₄) and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkynyl groups as well aspentynyl (C₅), hexynyl (C₆) and the like. Unless otherwise specified,each instance of an alkynyl group is independently unsubstituted (an“unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) withone or more substituents. In certain embodiments, the alkynyl group isan unsubstituted C₂₋₆ alkynyl. In certain embodiments, the alkynyl groupis a substituted C₂₋₆ alkynyl.

As used herein, a “saturated or unsaturated acyclic hydrocarbon” refersto radical of a saturated or unsaturated, straight-chain or branched,hydrocarbon group having from 1 to 20 carbon atoms and optionally one ormore carbon-carbon double or triple bonds. In certain embodiments, thehydrocarbon group is saturated. In some embodiments, the hydrocarbongroup is unsaturated, and contains one or more carbon-carbon double ortriple bonds. In some embodiments, the hydrocarbon group contains 1-10carbon atoms. In certain embodiments, the hydrocarbon group contains 1-5carbon atoms. In some embodiments, the hydrocarbon group contains 1-4carbon atoms. In some embodiments, the hydrocarbon group contains 1-3carbon atoms. In some embodiments, the hydrocarbon group contains 1-2carbon atoms.

As used herein, “carbocyclyl” refers to a radical of a nonaromaticcyclic hydrocarbon group having from 3 to 7 ring carbon atoms (“C₃₋₇carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms(“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Exemplary C₃₋₇ carbocyclylgroups include, without limitation, cyclopropyl (C₃), cyclopropenyl(C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅),cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl(C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇),cycloheptatrienyl (C₇), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing afused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”)) and can be saturated or can contain one or morecarbon-carbon double or triple bonds. “Carbocyclyl” also includes ringsystems wherein the carbocyclyl ring, as defined above, is fused withone or more aryl or heteroaryl groups wherein the point of attachment ison the carbocyclyl ring, and in such instances, the number of carbonscontinue to designate the number of carbons in the carbocyclic ringsystem. Unless otherwise specified, each instance of a carbocyclyl groupis independently unsubstituted (an “unsubstituted carbocyclyl”) orsubstituted (a “substituted carbocyclyl”) with 1, 2, 3, 4, or 5substituents as described herein. In certain embodiments, thecarbocyclyl group is an unsubstituted C₃₋₁₀ carbocyclyl. In certainembodiments, the carbocyclyl group is a substituted C₃₋₁₀ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 7 ring carbon atoms (“C₃₋₇cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 5 to 6 ring carbon atoms (“C₅₋₆ cycloalkyl”). Examples of C₅₋₆cycloalkyl groups include cyclopentyl (C₅) and cyclohexyl (C₅). Examplesof C₃₋₆ cycloalkyl groups include the aforementioned C₅₋₆ cycloalkylgroups as well as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₇cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇). Unless otherwise specified, each instance of acycloalkyl group is independently unsubstituted (an “unsubstitutedcycloalkyl”) or substituted (a “substituted cycloalkyl”) with one ormore substituents. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₇ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₇ cycloalkyl.

As used herein, alone or as part of another group, “heterocyclyl” refersto a radical of a 3 to 8-membered nonaromatic ring system having ringcarbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen and sulfur (“3-8-memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic heterocyclyl”)),and can be saturated or can contain one or more carbon-carbon double ortriple bonds. Heterocyclyl polycyclic ring systems can include one ormore heteroatoms in one or both rings. “Heterocyclyl” also includes ringsystems wherein the heterocycyl ring, as defined above, is fused withone or more carbocycyl groups wherein the point of attachment is eitheron the carbocycyl or heterocyclyl ring, or ring systems wherein theheterocyclyl ring, as defined above, is fused with one or more aryl orheteroaryl groups, wherein the point of attachment is on theheterocyclyl ring, and in such instances, the number of ring memberscontinue to designate the number of ring members in the heterocyclylring system.

In some embodiments, a heterocyclyl group is a 5-8 membered nonaromaticring system having ring carbon atoms and 1-4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen andsulfur (“5-8-membered heterocyclyl”). In some embodiments, aheterocyclyl group is a 5-6-membered nonaromatic ring system having ringcarbon atoms and 1-4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen and sulfur (“5-6-memberedheterocyclyl”). In some embodiments, the 5-6-membered heterocyclyl has1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In someembodiments, the 5-6-membered heterocyclyl has 1-2 ring heteroatomsselected from nitrogen, oxygen and sulfur. In some embodiments, the5-6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen,oxygen and sulfur. Exemplary 3-membered heterocyclyls containing 1heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.Exemplary 4 heterocyclyls containing 1 heteroatom include, withoutlimitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-memberedheterocyclyls containing 1 heteroatom include, without limitation,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclyls containing 2 heteroatoms include,without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary5-membered heterocyclyls containing 3 heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing 1 heteroatom include, withoutlimitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, andthianyl. Exemplary 6-membered heterocyclyl groups containing 2heteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing2 heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing 1 heteroatom include, withoutlimitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,azocanyl, oxecanyl and thiocanyl. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is an unsubstituted 3-8-membered heterocyclyl. Incertain embodiments, the heterocyclyl group is a substituted3-8-membered heterocyclyl.

As used herein, alone or as part of another group, “aryl” refers to aradical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2aromatic ring system having 6-10 ring carbon atoms and zero heteroatomsprovided in the aromatic ring system (“C₆₋₁₀ aryl”). In someembodiments, an aryl group has 6 ring carbon atoms (“C₆ aryl”; e.g.,phenyl). In some embodiments, an aryl group has 10 ring carbon atoms(“C₁₀ aryl”; e.g., naphthyl such as 1 and 2-naphthyl). “Aryl” alsoincludes ring systems wherein the aryl ring, as defined above, is fusedwith one or more cycloalkyl or heterocyclyl groups wherein the radicalor point of attachment is on the aryl ring, and in such instances, thenumber of carbon atoms continue to designate the number of carbon atomsin the aryl ring system. Unless otherwise specified, each instance of anaryl group is independently unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents asdescribed herein. In certain embodiments, the aryl group is anunsubstituted C₆₋₁₀ aryl. In certain embodiments, the aryl group is asubstituted C₆₋₁₀ aryl.

As used herein, alone or as part of another group, “heteroaryl” refersto a radical of a 5-14-membered monocyclic or polycyclic (e.g.,bicyclic) 4n+2 aromatic ring system having 4-10 ring carbon atoms and1-4 ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10-membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl polycyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocycyl or heterocycyl groups wherein the point of attachmentis on the heteroaryl ring, and in such instances, the number of ringmembers continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl or on theheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused polycyclic(aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein onering does not contain a heteroatom (e.g., indolyl, quinolinyl,carbazolyl and the like) the point of attachment can be on either ring,i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ringthat does not contain a heteroatom (e.g., 5-indolyl). In someembodiments, a heteroaryl group is a 5-10-membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-10-membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8-membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-8-membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6-membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-6-membered heteroaryl”). In someembodiments, the 5-6-membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen and sulfur. In some embodiments, the5-6-membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen and sulfur. In some embodiments, the 5-6-membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen and sulfur. Exemplary5-membered heteroaryls containing 1 heteroatom include, withoutlimitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-memberedheteroaryls containing 2 heteroatoms include, without limitation,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryls containing 3 heteroatomsinclude, without limitation, triazolyl, oxadiazolyl, thiadiazolyl.Exemplary 5-membered heteroaryls containing 4 heteroatoms include,without limitation, tetrazolyl. Exemplary 6 heteroaryls containing 1heteroatom include, without limitation, pyridinyl. Exemplary 6-memberedheteroaryls containing 2 heteroatoms include, without limitation,pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroarylscontaining 3 or 4 heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7 membered heteroaryls containing 1heteroatom include, without limitation, azepinyl, oxepinyl andthiepinyl. Exemplary 5,6-bicyclic heteroaryls include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryls include, without limitation,naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinoxalinyl, phthalazinyl and quinazolinyl. Unless otherwise specified,each instance of a heteroaryl group is independently unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is an unsubstituted 5-10-membered heteroaryl. In certainembodiments, the heteroaryl group is a substituted 5-10-memberedheteroaryl.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl, referred to without the suffix “-ene,” describe amonoradical of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,or heteroaryl, respectively, and as defined herein, wherein themonoradical is directly attached to a parent molecule or to anothergroup by one bond (e.g., one single or double bond). Monoradical groups,as defined herein, may also be optionally substituted. Groups referredto with the suffix “-ene”, such as alkylene, alkenylene, alkynylene,carbocyclylene, heterocyclylene, arylene and heteroarylene groups,describe a diradical of alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, respectively, and as defined herein,wherein the diradical is between and directly attached to two groups(e.g., between the parent molecule and another group) by two bonds(e.g., single or double bonds). Diradical groups may also be optionallysubstituted.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group (e.g., 1, 2, 3, 4, or 5 positions), and when morethan one position in any given structure is substituted, the substituentis either the same or different at each position. The term “substituted”is contemplated to include substitution with all permissiblesubstituents of organic compounds, any of the substituents describedherein that results in the formation of a stable compound. The presentinvention contemplates any and all such combinations in order to arriveat a stable compound. For purposes of this invention, heteroatoms suchas nitrogen may have hydrogen substituents and/or any suitablesubstituent as described herein which satisfy the valencies of theheteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(OR^(cc))R^(bb), —SH, —SR^(aa), —SSR^(cc), —C(═O)R^(aa),—CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa), —OC(═O)R^(aa), —OCO₂R^(aa),—C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂, —NR^(bb)C(═O)R^(aa),—NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —SC(═O)OR^(aa), —OC(═O)SR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇carbocyclyl, 3-8-membered heterocyclyl, C₆₋₁₀ aryl, and 5-10-memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8-membered heterocyclyl,C₆₋₁₀ aryl, and 5-10-membered heteroaryl, or two R^(aa) groups arejoined to form a 3-8-membered heterocyclyl or 5-10-membered heteroarylring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR′)OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R′, —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇carbocyclyl, 3-8-membered heterocyclyl, C₆₋₁₀ aryl, and 5-10-memberedheteroaryl, or two R^(bb) groups are joined to form a 3-8-memberedheterocyclyl or 5-10-membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8-memberedheterocyclyl, C₆₋₁₀ aryl, and 5-10-membered heteroaryl, or two R^(cc)groups are joined to form a 3-8-membered heterocyclyl or 5-10-memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(OR^(ee))R^(ff), —SH, —SR′, —SSR^(ee), —C(═O)R^(ee), —CO₂H,—C(═O)OR^(ee), —OC(═O)R^(ee), —OC(═O)OR^(ee), —C(═O)N(R^(ff))₂,—OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee),—NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee),—OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,—NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,—SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,—OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),—SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,—OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇carbocyclyl, 3-8-membered heterocyclyl, C₆₋₁₀ aryl, and 5-10-memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd) substituents canbe joined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8-membered heterocyclyl,C₆₋₁₀ aryl, and 5-10-membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8-memberedheterocyclyl, C₆₋₁₀ aryl, and 5-10-membered heteroaryl, or two R^(ff)groups are joined to form a 3-8-membered heterocyclyl or 5-10-memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups; and each instance of R^(gg) is,independently, halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, −OC₁₋₆ alkyl,—ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl),—N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl),—C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl), —OC(═O)(C₁₋₆ alkyl),—OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆alkyl), —NHC(═O)(C₁ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂,—C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆ alkyl,—C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂,—NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆alkyl), —SO₂NH₂, —SO₂C₁ alkyl, —SO₂OC₁₋₆ alkyl, —OSO₂C₁ alkyl, —SOC₁₋₆alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂,C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl,—SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl), —P(═O)(C₁₋₆ alkyl)₂,—OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8-membered-heterocyclyl, C₆₋₁₀ aryl,and 5-10-membered heteroaryl; or two geminal R^(gg) substituents can bejoined to form ═O or ═S.

In certain embodiments, the carbon atom substituent is selected from thegroup consisting of halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH,—OR^(aa), —N(R^(bb))₂, —SH, —SR^(aa), —C(═O)R^(aa), —CO₂H, —CHO,—CO₂R^(aa), —OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂,—OC(═O)N(R^(bb))₂, —NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa),—NR^(bb)C(═O)N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa), —NR^(bb)SO₂R^(aa),—SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —S(═O)R^(aa), —OS(═O)R^(aa),—Si(R^(aa))₃, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇ carbocyclyl,3-8-membered heterocyclyl, C₆₋₁₀ aryl, and 5-10-membered heteroaryl,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups;

As used herein, the term “hydroxyl” or “hydroxy” refers to the group—OH. The term “substituted hydroxyl” or “substituted hydroxy,” byextension, refers to a hydroxyl group wherein the oxygen atom issubstituted with a group other than hydrogen, e.g., selected from—OR^(aa), —ON(R^(bb))₂, —OC(═O)R^(aa), —OC(═O)SR^(aa), —OCO₂R^(aa),—OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa),—OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa), —OSO₂R^(aa), —OSi(R^(aa))₃,—OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa), —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and —OP(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein.

As used herein, the term “thiol” or “thio” refers to the group —SH. Theterm “substituted thiol” or “substituted thio,” by extension, refers toa thiol group wherein the sulfur atom is substituted with a group otherthan hydrogen, and includes groups selected from —SR^(aa), —S═SR^(cc),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —SC(═O)OR^(aa), and —SC(═O)R^(aa),wherein R^(aa) and R^(cc) are as defined herein.

As used herein, the term, “amino” refers to the group —NH₂.

As used herein, the term “substituted amino” refers to amonosubstituted, disubstituted, or trisubstituted amino group, asdefined herein.

As used herein, the term “monosubstituted amino” refers to an aminogroup substituted with one hydrogen and one group other than hydrogen,and includes groups selected from —NH(R^(bb)), —NHC(═O)R^(aa),—NHCO₂R^(aa), —NHC(═O)N(R^(bb))₂, —NHC(═NR^(bb))N(R^(bb))₂,—NHSO₂R^(aa), —NHP(═O)(OR^(cc))₂, and —NHP(═O)(NR^(bb))₂, whereinR^(aa), R^(bb) and R^(cc) are as defined herein, and wherein R^(bb) ofthe group —NH(R^(bb)) is not hydrogen.

As used herein, the term “disubstituted amino” refers to an amino groupsubstituted with two groups other than hydrogen, and includes groupsselected from —N(R^(bb))₂, —NR^(bb) (═O)R^(aa), NR^(bb)CO₂R^(aa),—NR^(bb)C(═O)N(R^(bb))₂, —NR^(bb)C(═NR^(bb))N(R^(bb))₂,NR^(bb)SO₂R^(aa), —NR^(bb)P(═O)(OR^(cc))₂, and —NR^(bb)P(═O)(NR^(bb))₂,wherein R^(aa), R^(bb), and R^(cc) are as defined herein, with theproviso that the nitrogen atom directly attached to the parent moleculeis not substituted with hydrogen.

As used herein, the term “sulfonyl” refers to a group selected from—S(═O)₂OH, —S(═O)₂N(R^(bb))₂, —S(═O)₂R^(aa), and —S(═O)₂OR^(aa), whereinR^(aa) and R^(bb) are as defined herein.

As used herein, the term “sulfinyl” refers to —S(═O)OH and —S(═O)R^(aa),wherein R^(aa) is as defined herein.

As used herein, the term “carbonyl” refers a group wherein the carbondirectly attached to the parent molecule is sp² hybridized, and issubstituted with an oxygen, nitrogen or sulfur atom, e.g., a groupselected from ketones (—C(═O)R^(aa)), carboxylic acids (—CO₂H),aldehydes (—CHO), esters (—CO₂R^(aa), —C(═O)SR^(aa), —C(═S)SR^(aa)),amides (—C(═O)N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))₂), andimines (—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa)),—C(═NR^(bb))N(R^(bb))₂), wherein R^(aa) and R^(bb) are as definedherein.

As used herein, the term “silyl” refers to the group —Si(R′)₃, whereinR^(aa) is as defined herein.

As used herein, the term “boronyl” refers to boranes, boronic acids,boronic esters, borinic acids, and borinic esters, e.g., boronyl groupsof the formula —B(R^(aa))₂, —B(OR^(cc))₂, and —BR^(aa)(OR^(cc)), whereinR^(aa) and R^(cc) are as defined herein.

As used herein, the term “phosphino” refers to the group —P(R^(cc))₃,wherein R^(cc) is as defined herein. An exemplary phosphino group istriphenylphosphine.

As used herein, the term “halo” or “halogen” refers to fluorine (fluoro,—F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

As used herein, “nitro” refers to the group —NO₂.

As used herein, “cyano” refers to the group —CN.

As used herein, “azido” refers to the group —N₃.

As used herein, “oxo” refers to the group ═O.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to an N atom are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

In certain embodiments, the substituent present on the nitrogen atom isan “amino protecting group”. Amino protecting groups include, but arenot limited to, —OH, —OR′, —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc) and R^(dd) are as defined herein. Amino protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,^(3rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

For example, amino protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxycarbonylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Amino protecting groups such as carbamate groups (e.g., —C(═O)OR^(aa))include, but are not limited to, methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Amino protecting groups such as sulfonamide groups (e.g., —S(═O)₂R^(aa))include, but are not limited to, p-toluenesulfonamide (Ts),benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), P3-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other amino protecting groups include, but are not limited to,phenothiazinyl-(10)-carbonyl derivative,N′-p-toluenesulfonylaminocarbonyl derivative, N′-phenylaminothiocarbonylderivative, N-benzoylphenylalanyl derivative, N-acetylmethioninederivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide,N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct (STABASE), 5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copperchelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on the oxygen atom is an“oxygen protecting group”. Oxygen protecting groups include, but are notlimited to —R^(aa), —N(R^(bb))₂, —C(═O)R^(aa), —C(═O)OR^(aa),—C(═O)SR^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R,—Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, the entirety of which isincorporated herein by reference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxyl)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethylcarbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC),2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethylcarbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate,p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate,3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzylcarbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate,methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxycarbonyl)benzoate, α-naphthoate,N,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate,dimethylphosphinothioyl, 2,4-dinitrophenylsulfenate, sulfate,methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). Forprotecting 1,2- or 1,3-diols, the protecting groups include methyleneacetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylideneketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylideneacetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal,cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal,2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal,2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethyleneacetal, dimethoxymethylene ortho ester, 1-methoxyethylidene ortho ester,1-ethoxyethylidine ortho ester, 1,2-dimethoxyethylidene ortho ester,α-methoxybenzylidene ortho ester, 1-(N,N-dimethylamino)ethylidenederivative, α-(N,N′-dimethylamino)benzylidene derivative,2-oxacyclopentylidene ortho ester, di-t-butylsilylene group (DTBS),1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS),tetra-t-butoxydisiloxane-1,3-diylidene derivative (TBDS), cycliccarbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

In certain embodiments, the substituent present on an sulfur atom is ansulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

These and other exemplary substituents are described in more detail inthe Detailed Description, the Examples and in the Claims. The inventionis not intended to be limited in any manner by the above exemplarylisting of substituents.

As used herein, the terms “salt”, “acceptable salt”, or“pharmaceutically acceptable salt” refers to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, Berge et al., describespharmaceutically acceptable salts in detail in J. PharmaceuticalSciences (1977) 66:1-19. Pharmaceutically acceptable salts of thecompounds of this invention include those derived from suitableinorganic and organic acids and bases. Examples of pharmaceuticallyacceptable, nontoxic acid addition salts are salts of an amino groupformed with inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citricacid, succinic acid or malonic acid or by using other methods used inthe art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N+(C₁₋₄alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

As used herein, the term “prodrug” means a compound that can hydrolyze,oxidize, or otherwise react under biological conditions (e.g., in vitroor in vivo enzymatic conditions) to provide a pharmacologically activecompound. In certain cases, a prodrug has improved physical and/ordelivery properties over the parent compound. Prodrugs are typicallydesigned to enhance pharmacologically, pharmaceutically and/orpharmacokinetically based properties associated with the parentcompound. The advantage of a prodrug can lie in its physical properties,such as enhanced water solubility for parenteral administration atphysiological pH compared to the parent compound, or it enhancesabsorption from the digestive tract, or it may enhance drug stabilityfor long-term storage.

Other Definitions

“Disease”, “disorder,” and “condition” are used interchangeably herein.

As used herein, an “individual” or “subject” to which administration iscontemplated includes, but is not limited to, humans (i.e., a male orfemale of any age group, e.g., a pediatric subject (e.g., child,adolescent) or adult subject (e.g., young adult, middle-aged adult orsenior adult)), other primates (e.g., cynomolgus monkeys, rhesusmonkeys) and commercially relevant mammals such as cattle, pigs, horses,sheep, goats, cats, and/or dogs. In any aspect and/or embodiment of theinvention, the mammal is a human.

As used herein, “local administration” or “administering locally” or“local effect” means administration/application of the active ingredientor active metabolite thereof directly, or in proximity to, a part of thebody, tissue, or lesion where said active substance is intended to exertits action. This may include, for example, topical administration to apart of the skin.

As used herein, unless otherwise specified, “topical administration” or“topically” means application to the surface of the skin, e.g., in anon-invasive manner.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” “an amount sufficient” or “sufficient amount” of acompound means the level, amount or concentration of the compound neededto treat a disease, disorder or condition, or to reduce or lower aparticular parameter (e.g., body fat) in the body of a subject, withoutcausing significant negative or adverse side effects to body or thetreated tissue. The term “therapeutically effective amount” canencompass an amount that improves overall therapy, reduces or avoidssymptoms or causes of disease or condition, or enhances the therapeuticefficacy of another therapeutically active agent.

As used herein, the terms “reduce”, “reduction”, “reducing”, “lower”, or“lowering” means to diminish or lessen the volume, size, mass, bulk,density, amount, and/or quantity of a substance (e.g., body fat, adiposetissue) in the body of a subject.

As used herein, the term “eliminate” means to completely remove anyunwanted or undesired volume, size, mass, bulk, density, amount, and/orquantity of a substance (e.g., excess body fat, excess adipose tissue)in the body of a subject.

As used herein, “suffer”, “suffers” or “suffering from” refers to asubject diagnosed with a particular disease or condition. As usedherein, “likely to suffer” refers to a subject who has not beendiagnosed with a particular disease or condition by a medicalpractitioner, but has a predisposition (e.g., genetic and/or physiologicpredisposition), or exhibits signs or symptoms of the disease orcondition.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease or condition, whichreduces the severity of the disease or condition, or retards or slowsthe progression of the disease or condition.

As used herein, unless otherwise specified, the terms “prevent,”“preventing” and “prevention” contemplate an action that occurs before asubject begins to suffer from the specified disease or condition, whichinhibits or reduces the severity of the disease or condition.

Conditions for which treatment and prevention are contemplated may befurther classified as a medical condition or a cosmetic condition. A“medical condition,” as used herein, refers to an abnormal conditionthat affects the body. A “cosmetic condition,” as used herein, refers toa condition other than a medical condition that affects the physicalappearance of the body. A cosmetic condition can occur, for example, dueto normal processes in a body, such as aging, pregnancy, puberty, andexposure to the sun or the elements, or due to normal features of abody, such as inherited facial features or body shapes that are found inhealthy individuals. Various medical and cosmetic conditions aredescribed herein. A “cosmetic method” refers to a method or procedureintended to ameliorate a cosmetic condition in the subject, e.g., forthe beautification of the subject's body or a part thereof, and a“cosmetic composition” is contemplated useful for such purpose. A“therapeutic method” refers to a method or procedure intended to treator prevent a medical condition, and a “pharmaceutical composition” iscontemplated useful for such purpose. However, while pharmaceuticalcompositions are contemplated useful for therapeutic and prophylacticpurposes, and cosmetic compositions are contemplated useful for cosmeticpurposes, there is overlap between the two compositions in terms of useof the composition. For example, a pharmaceutical composition is alsocontemplated useful for beautification purposes.

As used herein, unless otherwise specified, “excess submental fat” meansexcess fat on the body region including the mentum, the underside of thejaw, and the anterior neck, for example to the level of the inferiorborder of the cricoid.

As used herein, unless otherwise specified, “steatoblepharon” refers toa condition characterized by excess fat of the eyelids and/orperiorbital tissue. The excess fat can be due to prolapse of orbital orperiorbital fat. Steatoblepharon can occur in the lower or upper eyelid,or both. Steatoblepharon can be considered a cause of “eye bags.”

The presence, amount, or severity of excess fat can be assessedobjectively, e.g., by magnetic resonance imaging, computed tomography,biopsy, or skin calipers, or subjectively, e.g., by a clinician, apatient, or other observer, optionally with reference to a photonumeric,verbal, or descriptive scale or classification system, e.g., a five-stepseverity scale.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present invention relates to new, stable, manufacturable,well-tolerated, aesthetically pleasing compositions that, when topicallyapplied to the skin, delivers a therapeutically effective amount of aprostaglandin FP receptor agonist (PFPRA compound), e.g., aprostaglandin F2α analog, e.g., latanoprost or tafluprost, tosubcutaneous fat. More specifically, the invention relates tocompositions for delivery of a PFPRA compound to subcutaneous fatcomprising a PFPRA compound and a fatty acid ester, e.g., isopropylmyristate. The formulations are useful for local reduction ofsubcutaneous fat, and for other therapeutic uses as described herein.The invention also relates to methods for locally reducing body fat,comprising administering the inventive compositions to the skin. Theinvention also related to a process for manufacturing one or more of theinventive compositions, e.g., in a sterile fashion, whereby thecomposition is sterile, endotoxin-free, and ophthalmically compatible,and therefore suitable for use on the eyelid or near the eye. Aparticular advantage of the inventive formulations is suitability forapplication on the face and/or periorbital skin.

As described herein, no theoretical framework was available to theinventors to select or improve a composition for delivering a PFPRAcompound to subcutaneous fat. Rather, the inventors found it necessaryto test a wide range of conditions both in vitro and in vivo, withdifferent formulation components at different concentrations and indifferent combinations. This testing led to the discovery that inclusionof a fatty acid ester (e.g., isopropyl myristate) in the compositionconferred exceptionally better performance for delivery of a PFPRAcompound and reduction of subcutaneous fat compared to, for example, useof 1,3-butanediol, diethylene glycol monoethyl ether, dimethylsulfoxide,ethanol, glycerol monooleate, hydroxypropyl cellulose, lauryl lactate,methyl laurate, oleyl alcohol, polysorbate 80, propylene glycol, andcombinations thereof.

Without wishing to be bound by any particular theory, the specialproperties conferred by combining a fatty acid ester (e.g., isopropylmyristate) and a PFPRA may owe to certain similarities between the fattyacid ester (e.g., isopropyl myristate) and PFPRA compounds, i.e.,similar structure and similar polarity. For example, latanoprost (cf.Examples 1-3) and isopropyl myristate are both isopropyl esters withparent acids comprising aliphatic tails of similar chain length(isopropyl myristate, 13 aliphatic carbons in the lipid tail;latanoprost, 13 aliphatic carbons if the cyclizing carbons 9 through 11of the cyclopentyl ring are not counted). As shown in FIG. 1, in theirenergy-minimized 3-dimensional conformations, both compounds are roughlylinear and of similar length. Furthermore, according to this structuralhypothesis, latanoprost per se could serve as a penetration enhancer inthis context, in that the 5-cis double bond of latanoprost (likewisepresent in most other PFPRA compounds) may lend particular improvementto the penetration characteristics of isopropyl myristate, as thestructural kink of unsaturated molecules is known to interfere withclose packing of the phospholipid bilayer and can thereby improvepenetration.

In some embodiments, the composition comprises a PFPRA compound with a5-cis double bond. In some embodiments, the composition comprises aPRPRA compound ester and a fatty acid ester, wherein both esterscomprise the same ether (—OR^(FA1)) moiety. In some embodiments, thecomposition comprises a PRPRA compound ester and a fatty acid ester,wherein both esters comprise aliphatic tails (R^(FA2)) of similar chainlength.

In some embodiments, the composition comprises isopropyl myristate. Insome embodiments, the composition comprises isopropyl myristate and oneor more additional different fatty acid esters, e.g., of the belowformula, wherein the ether moiety of the ester (R^(FA1)) is optionallysubstituted C₁-C₆ alkyl, and the aliphatic moiety of the ester (R^(FA2))is optionally substituted C₁₀-C₂₀ alkyl or optionally substitutedC₁₀-C₂₀ alkenyl, and wherein the additional different fatty acid esteris not isopropyl myristate. It is understood that, according to theabove theory, a different fatty acid ester may be used in thecomposition other than isopropyl myristate, e.g., such that thecomposition comprises a fatty acid ester of the below formula, whereinthe ether moiety of the ester (R^(FA1)) is optionally substituted C₁-C₆alkyl, and the aliphatic moiety of the ester (R^(FA2)) is optionallysubstituted C₁₀-C₂₀ alkyl or optionally substituted C₁₀-C₂₀ alkenyl,provided the composition does not comprise isopropyl myristate.Alternatively, in some embodiments, isopropyl myristate cannot bereplaced with a different fatty acid ester. In some embodiments, thecomposition comprises isopropyl myristate and does not comprise one ormore additional different fatty acid esters.

In certain embodiments, R^(FA1) is an optionally substituted C₁₋₅alkyl,C₁₋₄alkyl, C₁₋₃alkyl, C₁₋₂alkyl, C₂₋₆alkyl, C₂₋₅alkyl, C₂₋₄alkyl,C₂₋₃alkyl, C₃₋₆alkyl, C₃₋₅alkyl, C₃₋₄alkyl, C₄₋₆alkyl, C₄₋₅alkyl, orC₅₋₆alkyl. In certain embodiments, R^(FA1) is a branched alkyl group,e.g., for example, isopropyl, isobutyl, sec-butyl, tert-butyl, orneopentyl. In certain embodiments, R^(FA1) is an unbranched alkyl group,e.g., for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, orn-hexyl. In certain embodiments, R^(FA1) is an unsubstituted alkylgroup, i.e., comprising only carbon and hydrogen atoms. In certainembodiments, R^(FA1) is a substituted alkyl group, e.g., substituted byhalogen atoms.

In certain embodiments, R^(FA2) is an optionally substituted C₁₀-C₁₉alkyl, C₁₀-C₁₈ alkyl, C₁₀-C₁₇ alkyl, C₁₀-C₁₆ alkyl, C₁₀-C₁₅ alkyl,C₁₀-C₁₄ alkyl, C₁₀-C₁₃ alkyl, C₁₁-C₂₀ alkyl, C₁₁-C₁₉ alkyl, C₁₁-C₁₈alkyl, C₁₁-C₁₇ alkyl, C₁₁-C₁₆ alkyl, C₁₁-C₁₅ alkyl, C₁₁-C₁₄ alkyl,C₁₁-C₁₃ alkyl, C₁₂-C₁₉ alkyl, C₁₂-C₁₈ alkyl, C₁₂-C₁₇ alkyl, C₁₂-C₁₆alkyl, C₁₂-C₁₅ alkyl, C₁₂-C₁₄ alkyl, C₁₂-C₁₃ alkyl, C₁₃-C₂₀ alkyl,C₁₃-C₁₉ alkyl, C₁₃-C₁₈ alkyl, C₁₃-C₁₇ alkyl, C₁₃-C₁₆ alkyl, C₁₃-C₁₅alkyl, C₁₃-C₁₄ alkyl, C₁₄-C₂₀ alkyl, C₁₄-C₁₉ alkyl, C₁₄-C₁₈ alkyl,C₁₄-C₁₇ alkyl, C₁₄-C₁₆ alkyl, C₁₄-C₁₅ alkyl, C₁₅-C₂₀ alkyl, C₁₅-C₁₉alkyl, C₁₅-C₁₈ alkyl, C₁₅-C₁₇ alkyl, or C₁₅-C₁₆ alkyl. In certainembodiments, R^(FA2) is a straight chain (unbranched) alkyl group. Incertain embodiments, R^(FA2) is an unsubstituted alkyl group, i.e.,comprising only carbon and hydrogen atoms. In certain embodiments,R^(FA2) is a substituted alkyl group, e.g., substituted by halogenatoms.

In certain embodiments, R^(FA2) is an optionally substituted C₁₀-C₁₉alkenyl, C₁₀-C₁₈ alkenyl, C₁₀-C₁₇ alkenyl, C₁₀-C₁₆ alkenyl, C₁₀-C₁₅alkenyl, C₁₀-C₁₄ alkenyl, C₁₀-C₁₃ alkenyl, C₁₁-C₂₀ alkenyl, C₁₁-C₁₉alkenyl, C₁₁-C₁₈ alkenyl, C₁₁-C₁₇ alkenyl, C₁₁-C₁₆ alkenyl, C₁₁-C₁₅alkenyl, C₁₁-C₁₄ alkenyl, C₁₁-C₁₃ alkenyl, C₁₂-C₁₉ alkenyl, C₁₂-C₁₈alkenyl, C₁₂-C₁₇ alkenyl, C₁₂-C₁₆ alkenyl, C₁₂-C₁₅ alkenyl, C₁₂-C₁₄alkenyl, C₁₂-C₁₃ alkenyl, C₁₃-C₂₀ alkenyl, C₁₃-C₁₉ alkenyl, C₁₃-C₁₈alkenyl, C₁₃-C₁₇ alkenyl, C₁₃-C₁₆ alkenyl, C₁₃-C₁₅ alkenyl, C₁₃-C₁₄alkenyl, C₁₄-C₂₀ alkenyl, C₁₄-C₁₉ alkenyl, C₁₄-C₁₈ alkenyl, C₁₄-C₁₇alkenyl, C₁₄-C₁₆ alkenyl, C₁₄-C₁₅ alkenyl, C₁₅-C₂₀ alkenyl, C₁₅-C₁₉alkenyl, C₁₅-C₁₈ alkenyl, C₁₅-C₁₇ alkenyl, C₁₅-C₁₆ alkenyl. In certainembodiments, R^(FA2) is an unbranched alkenyl group. In certainembodiments, R^(FA2) is an unsubstituted alkenyl group, i.e., comprisingonly carbon and hydrogen atoms. In certain embodiments, R^(FA2) is asubstituted alkenyl group, e.g., substituted by halogen atoms. Incertain embodiments, R^(FA2) is an alkenyl group comprising 1, 2, 3, or4 double bonds, each independently cis or trans.

In certain embodiments, R^(FA2) is selected from any one of thefollowing saturated or unsaturated fatty acyl moieties:

Lauric —(CH₂)¹⁰CH₃,

Myristic —(CH₂)₁₂CH₃,

Palmitic —(CH₂)₁₄CH₃,

Stearic —(CH₂)₁₆CH₃,

Myristoleic —(CH₂)₇CH═CH(CH₂)₃CH₃,

Palmitoliec —(CH₂)₇CH═CH(CH₂)₅CH₃,

Sapienic —(CH₂)₄CH═CH(CH₂)₈CH₃,

Oleic —(CH₂)₇CH═CH(CH₂)₇CH₃,

Linoleic —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃,

α-Linolenic —(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃.

In certain embodiments, the total number of carbons atoms in the fattyacid ester, which include the number of carbons of R^(FA1) and R^(FA2)is between 15 and 19, inclusive, i.e., 15, 16, 17, 18, or 19 carbonatoms total.

In some embodiments, the total number of carbons in the fatty acid esteris selected to approximate the aliphatic chain length of the PFPRAcompound. For example, in certain embodiments, the PRPRA compound hasthe same number of total carbon atoms in the sum of the aliphatic chainand ester moiety of the PFPRA compound, i.e., 15, 16, 17, 18, or 19carbon atoms total.

In some embodiments, fatty acid ester is selected such that itspredicted length (e.g. by molecular modeling) is similar (e.g., within±3 Å) to the predicted length of the PFPRA compound. For example,isopropyl myristate has a predicted length (between the two most distantheavy atoms) of about 20 Å, which compares favorably with a length ofabout 18 Å for latanoprost and tafluprost, about 19 Å for bimatoprost,and about 20 Å for travoprost. In some embodiments, the predicted lengthis in an energy-minimized conformation. In some embodiments, thepredicted length is of a conformation whereby freely rotating bonds arerotated as to provide a maximal length.

In certain embodiments, the composition further comprises an ointmentbase. As used herein, an ointment is a homogeneous, viscous, semi-solidpreparation, which comprises a greasy, ointment base having amedium-to-high viscosity, that is intended for topical application tothe skin. Exemplary ointment bases include, but are not limited to,hydrocarbon bases/waxes (e.g., plant and animal waxes (e.g., beeswax,lanolin, carnauba wax), petroleum derived waxes (e.g., hard paraffin waxor soft paraffin wax, i.e., petroleum jelly), microcyrstalline wax,ceresine wax, white wax, yellow wax, and cetyl esters wax). In certainembodiments, the ointment base is a hydrocarbon base, e.g., softparaffin wax, e.g., petroleum jelly. Petroleum jelly (also known aspetrolatum, white petrolatum, soft paraffin or multi-hydrocarbon) is asemi-solid preparation typically comprising (or consisting of) one ormore saturated hydrocarbons with carbon numbers mainly higher than 25(typically 25 to 50, such as 25 to 40, such as 25 to 35). It typicallyhas a boiling point of from about 250° C. to about 350° C., such asabout 280° C. to about 320° C., preferably about 300° C., and a meltingpoint typically from about 36° C. to about 60° C. In certainembodiments, the petroleum jelly is obtained in sterile form or issterilized prior to manufacturing the composition. In certainembodiments, the petroleum jelly is pure ultra white petroleum jelly.

In some embodiments, the composition further comprises an organicalcohol, e.g., methanol, ethanol, propanol, isopropanol, 1,3-butanediol,ethylene glycol, or propylene glycol. In certain embodiments, theorganic alcohol is propylene glycol. However, in certain embodiments,1,3-butanediol is excluded.

In clinical practice, topical delivery of compounds across the skinusually relies on the principle of passive diffusion. This principledictates that a compound can only flow from an area of higherthermodynamic potential to one of lower thermodynamic potential. Asolute held firmly by a vehicle will demonstrate little or no diffusion.Thus, the skilled artisan expects that a PFPRA compound (which is anoil-soluble compound) will penetrate better from an aqueous vehicle thanfrom an oily vehicle (See, e.g., Barrett C W, Skin penetration. J. Soc.Cosmetic Chemists 1969; 20:487-499). Thus far, this theory has beenborne out in practice, as PFPRA compound formulations for topical usehave repeatedly selected water or ethanol as the preferred carrier forclinical use. See, e.g., prescribing inserts for Xalatan®, Travatan®,Lumigan®, and Zioptan®. See also Blume-Peytavi U et al, A randomizeddouble-blind placebo-controlled pilot study to assess the efficacy of a24-week topical treatment by latanoprost 0.1% on hair growth andpigmentation in healthy volunteers with androgenetic alopecia, J Am AcadDermatol 2012; 66:794-800. Thus, another surprising aspect of theinvention is that compositions comprising PFPRA compound formulated witha fatty acid ester (e.g., isopropyl myristate) and an ointment base,e.g., a hydrocarbon base such as petroleum jelly, delivers the PFPRAcompound more effectively than an array of other vehicles, as disclosedherein. In certain embodiments, the composition does not include anaqueous or water-soluble component such as an organic alcohol. However,in certain embodiments, the composition does comprise an organicalcohol, e.g., propylene glycol, and, in certain embodiments, thecomposition comprises the organic alcohol in no greater than 50% byweight. In certain embodiments, the composition is hydrophobic, e.g.,the composition is not miscible in water. In certain embodiments, thecomposition is not an emulsion. In certain embodiments, the compositiondoes not contain mineral oil.

PFPRA Compounds

As used herein, a “PFPRA compound” can be any therapeutically relevant,naturally occurring or synthetic prostaglandin or prostaglandin analog,provided that it or its active metabolite (e.g., if an ester, the parentacid) suitably agonizes a prostaglandin FP receptor in a suitablefunctional assay. As used herein, a suitable degree of agonism can bedefined, for example, as a half maximal effective concentration (EC₅₀)of 1 micromolar or less, preferably 100 nanomolar or less. A suitablefunctional assay can be, for example, assessment of phosphoinositideturnover in HEK293 cells expressing a cloned FP prostaglandin receptor.See, e.g., Sharif et al., J. Ocular Pharmacol. Ther. 2002; 18:313-324.Many PFPRA compounds can be classified as prostaglandins, prostanoids,or prostamides. Naturally occurring prostaglandins are a class ofstructurally related eicosanoid hormones that are derived enzymaticallyfrom arachidonic acid. An example of a naturally occurring prostaglandinPFPRA compound is prostaglandin F2a. Exemplary synthetic prostaglandins,which are prostaglandin F2a analogs, include, but are not limited to,latanoprost, latanoprost free acid, bimatoprost, bimatoprost free acid,tafluprost, tafluprost free acid, travoprost, travoprost free acid(a.k.a. fluprostenol), and prodrugs (e.g., 9-, 11-, and/or 15-esterderivatives) thereof.

In certain embodiments, the PFPRA compound is a compound of Formula (I)or (II):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof;wherein:

L is of the formula:

-   -   each instance of        independently represents a single bond or a double bond, which        can be in the cis or trans configuration;

A is optionally substituted C₁₋₁₀alkylene, optionally substitutedC₂₋₁₀alkenylene, or optionally substituted C₂₋₁₀ alkynylene, wherein thealkylene, alkenylene, or alkynylene group is optionally interrupted byone or more —O— or —S— groups;

B is hydrogen, optionally substituted C₃₋₇carbocyclyl, optionallysubstituted 3-8-membered-heterocyclyl, optionally substituted5-14-membered-heteroaryl, optionally substituted C₆₋₁₀aryl, optionallysubstituted C₁₋₃₀alkyl, optionally substituted C₂₋₃₀alkenyl, oroptionally substituted C₂₋₃₀alkynyl;

X is —OR₄, —SR₄, or —N(R₄)₂, wherein each instance of R₄ isindependently hydrogen, optionally substituted C₁₋₃₀alkyl, optionallysubstituted C₂₋₃₀alkenyl, optionally substituted C₂₋₃₀alkynyl, —C(═O)R₅,or —C(═O)OR₅, wherein R₅ is optionally substituted C₁₋₃₀alkyl,optionally substituted C₂₋₃₀alkenyl, or optionally substitutedC₂₋₃₀alkynyl, or two R₄ groups are joined to form an optionallysubstituted 3-8-membered-heterocyclyl or optionally substituted5-14-membered-heteroaryl ring;

Z is ═O, ═S, or ═NR_(Z), wherein R_(Z) is selected from hydrogen, anamino protecting group, —OH, substituted hydroxyl, optionallysubstituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇carbocyclyl,optionally substituted 3-8-membered-heterocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl, or Zrepresents two hydrogen atoms;

-   -   with regard to the compound of Formula (I), one of R₁ and R₂ is        ═O, —OH, or a —O(CO)R₆ group and the other one is —OH or        —O(CO)R₆, or R₁ is ═O and R₂ is H, wherein R₆ is an optionally        substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,        optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₇ wherein m        is 0 or an integer of between 1-10, inclusive, and R₇ is        optionally substituted C₃₋₇ carbocyclyl, optionally substituted        3-8-membered-heterocyclyl, optionally substituted C₆₋₁₀aryl, or        optionally substituted 5-14-membered-heteroaryl; and with regard        to the compound of Formula (II), R₁ is ═O, —OH, or —O(CO)R₆,        wherein R₆ is a an optionally substituted C₁₋₂₀alkyl, optionally        substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀alkynyl,        or —(CH₂)_(m)R₇ wherein m is 0 or an integer of between 1-10,        inclusive, and R₇ is optionally substituted C₃₋₇ carbocyclyl,        optionally substituted 3-8-membered-heterocyclyl, optionally        substituted C₆₋₁₀aryl, or optionally substituted        5-14-membered-heteroaryl.

In certain embodiments, the endocyclic dotted lines of Formula (I)(i.e., depicted in the 5-membered ring) each represent a single bond.

For example, in certain embodiments, wherein the endocyclic dotted linesof Formula (I) each represent a single bond, provided is a compoundhaving any one of the following stereochemistry:

pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof, wherein

, R₁, R₂, A, B, Z and X are as defined herein.

In certain embodiments, the exocyclic dotted line

(i.e., depicted outside of the 5-membered ring) of Formula (I) or (II)or a subset thereof represents a double bond in the cis or transconfiguration. In certain embodiments, the exocyclic dotted line

represents a double bond in the cis configuration.

In certain embodiments, each instance of

independently represents a single bond or a double bond, which can be inthe cis or trans configuration.

As generally defined above, one of R₁ and R₂ is ═O, —OH, or a —O(CO)R₆group, and the other is —OH or —O(CO)R₆, or R₁ is ═O, and R₂ is H,wherein R₆ is an optionally substituted C₁₋₂₀alkyl, optionallysubstituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, or—(CH₂)_(m)R₇, wherein m is 0 or an integer of between 1-10, inclusive,and R₇ is optionally substituted C₃₋₇carbocyclyl, optionally substituted3-8-membered-heterocyclyl, optionally substituted C₆₋₁₀aryl, oroptionally substituted 5-14-membered-heteroaryl.

In certain embodiments, R₁ is ═O, and R₂ is H.

In certain embodiments, one of R₁ and R₂ is —OH, substituted hydroxyl,or —O(CO)R₆, and the other is —OH, substituted hydroxyl, or —O(CO)R₆.

In certain embodiments, both R₁ and R₂ are —OH.

In certain embodiments, one of R₁ and R₂ is —OH, and the other is—O(CO)R₆. In certain embodiments, R₁ is —OH, and R₂ is —O(CO)R₆. Incertain embodiments, R₂ is —OH, and R₁ is —O(CO)R₆. In certainembodiments, R₆ is an optionally substituted C₁₋₂₀alkyl, e.g.,optionally substituted C₁₋₁₅alkyl, optionally substituted C₁₋₁₀alkyl,optionally substituted C₁₋₈alkyl, optionally substituted C₁₋₆alkyl,optionally substituted C₁₋₅alkyl, optionally substituted C₁₋₄alkyl,optionally substituted C₁₋₃alkyl, or optionally substituted C₁₋₂alkyl.In certain embodiments, R₆ is —(CH₂)_(r)CH₃, wherein r is 0, 1, 2, 3, 4,5, or 6, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃.

As generally defined above, A is optionally substituted C₁₋₁₀alkylene,optionally substituted C₂₋₁₀alkenylene, or optionally substitutedC₂₋₁₀alkynylene, wherein the alkylene, alkenylene, or alkynylene groupis optionally interrupted by one or more —O— or —S— groups.

In certain embodiments, A is optionally substituted C₁₋₁₀alkylene,optionally substituted C₂₋₁₀alkenylene or optionally substitutedC₂₋₁₀alkynylene, wherein the alkylene, alkenylene, or alkynylene groupis optionally interrupted by one —O— group.

In certain embodiments, A is optionally substituted C₄₋₆alkylene,optionally substituted C₄₋₆alkenylene or optionally substitutedC₄₋₆alkynylene, wherein the alkylene, alkenylene, or alkynylene group isoptionally interrupted by one —O— group.

In certain embodiments, A is optionally substituted C₄₋₆alkyleneoptionally interrupted by one —O— group. In certain embodiments, A isoptionally substituted C₄₋₆alkenylene optionally interrupted by one —O—group. In certain embodiments, A is optionally substitutedC₄₋₆alkynylene optionally interrupted by one —O— group.

In certain embodiments, A is substituted with one or more groupsselected from the group consisting of halogen, —OH, substitutedhydroxyl, or —O(CO)R₈, wherein R₈ is optionally substituted C₁₋₂₀alkyl,optionally substituted C₂₋₂₀alkenyl, optionally substitutedC₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 or an integer between 1-10,inclusive, and R₉ is optionally substituted C₃₋₇carbocyclyl, optionallysubstituted C₆₋₁₀aryl, and optionally substituted5-14-membered-heteroaryl.

In certain embodiments, A is substituted with ═O.

In certain embodiments, A is substituted with —OC(═O)R₈, wherein R₈ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉, wherein m is 0 oran integer between 1-10, inclusive, and R₉ is optionally substitutedC₃₋₇carbocyclyl, optionally substituted C₆₋₁₀aryl, or optionallysubstituted 5-14-membered-heteroaryl.

In certain embodiments, A is substituted with —OH or substitutedhydroxyl.

In certain embodiments, A is substituted with substituted hydroxyl.

In certain embodiments, A is substituted with —OH.

In certain embodiments, A is of the Formula (i), (ii), (iii), (iv), (v),or (vi):

wherein each instance of

independently represents a single bond or a double bond, which can be inthe cis or trans configuration;

-   -   each instance of R₃ and R₃′ is hydrogen, halogen, —OH,        substituted hydroxyl, or —O(CO)R₈, wherein R₈ is optionally        substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,        optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉, wherein m        is 0 or an integer between 1-10, inclusive, and R₉ is optionally        substituted C₃₋₇carbocyclyl, optionally substituted C₆₋₁₀aryl,        or optionally substituted 5-14-membered-heteroaryl, or R₃ and        R₃′ are joined to form ═O;

G is —O— or —S—;

y is 0, 1, or 2; and

x is 0 or 1.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments,

of Formula (i), (ii), or (iii) represents a double bond in the cisconfiguration.

In certain embodiments,

of Formula (i), (ii), or (iii) represents a double bond in the transconfiguration.

In certain embodiments, the group of the Formula (i) is of the formula:

In certain embodiments, the group of the Formula (ii) is of the formula:

In certain embodiments,

of Formula (i), (ii), or (iii) represents a single bond.

In certain embodiments, the group of the Formula (i) is of the formula:

In certain embodiments, the group of the Formula (ii) is of the formula:

As generally defined above, each instance of R₃ and R₃′ is independentlyhydrogen, halogen, —OH, substituted hydroxyl, or —O(CO)R₈, wherein R₈ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 oran integer between 1-10, inclusive, and R₉ is optionally substitutedC₃₋₇carbocyclyl, optionally substituted C₆10 aryl, or optionallysubstituted 5-14-membered-heteroaryl; or R₃ and R₃′ are joined to form═O.

In certain embodiments, R₃ is hydrogen. In certain embodiments, R₃′ ishydrogen. In certain embodiments, R₃ is hydrogen and R₃′ is anon-hydrogen group. In certain embodiments, R₃′ is hydrogen and R₃ is anon-hydrogen group. In certain embodiments, however, neither R₃ nor R₃′is hydrogen.

In certain embodiments, R₃ and R₃′ are joined to form ═O.

In certain embodiments, R₃ and R₃′ are the same group. In certainembodiments, R₃ and R₃′ are different groups.

In certain embodiments, R₃ is —OH, substituted hydroxyl, or —O(CO)R₈,wherein R₈ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉wherein m is 0 or an integer between 1-10, inclusive, and R₉ isoptionally substituted C₃₋₇carbocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl. Incertain embodiments, R₃ is —O(CO)R₈. In certain embodiments, R₃ is—O(CO)R₈, and R₈ is optionally substituted C₁₋₂₀alkyl, e.g., optionallysubstituted C₁₋₁₅alkyl, optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₁₋₁₅alkyl, optionally substituted C₁₋₆alkyl, optionallysubstituted C₁₋₅alkyl, optionally substituted C₁₋₄alkyl, optionallysubstituted C₁₋₃alkyl, or optionally substituted C₁₋₂alkyl. In certainembodiments, R₃ is —O(CO)R₈, and R₈ is —(CH₂)_(q)CH₃ wherein q is 0, 1,2, 3, 4, 5, or 6, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃. Incertain embodiments, R₃ is —OH or substituted hydroxyl. In certainembodiments, R₃ is substituted hydroxyl. In certain embodiments, R₃ is—OH.

In certain embodiments, R₃′ is —OH, substituted hydroxyl, or —O(CO)R₈,wherein R₈ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉wherein m is 0 or an integer between 1-10, inclusive, and R₉ isoptionally substituted C₃₋₇carbocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl. Incertain embodiments, R₃′ is —O(CO)R₈. In certain embodiments, R₃′ is—O(CO)R₈, and R₈ is optionally substituted C₁₋₂₀alkyl, e.g., optionallysubstituted C₁₋₁₅alkyl, optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₁₋₁₅alkyl, optionally substituted C₁₋₆alkyl, optionallysubstituted C₁₋₅alkyl, optionally substituted C₁₋₄alkyl, optionallysubstituted C₁₋₃alkyl, or optionally substituted C₁₋₂alkyl. In certainembodiments, R₃′ is —O(CO)R₈, and R₈ is —(CH₂)_(q)CH₃, wherein q is 0,1, 2, 3, 4, 5, or 6, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃.In certain embodiments, R₃′ is —OH or substituted hydroxyl. In certainembodiments, R₃′ is substituted hydroxyl. In certain embodiments, R₃′ is—OH.

In certain embodiments, R₃ is halogen, e.g., selected from fluoro,chloro, bromo, and iodo. In certain embodiments, R₃′ is halogen, e.g.,selected from fluoro, chloro, bromo, and iodo. In certain embodiments,R₃ is halogen and R₃′ is halogen, e.g., each independently selected fromfluoro, chloro, bromo, and iodo. In certain embodiments, both R₃ and R₃′are fluoro.

In certain embodiments, y is 0; and x is 1. In certain embodiments, y is0; and x is 0. In certain embodiments, y is 1; and x is 1. In certainembodiments, y is 1; and x is 0. In certain embodiments, y is 2; and xis 0. In certain embodiments, y is 2; and x is 1.

As defined generally above, B is hydrogen, optionally substitutedC₃₋₇carbocyclyl, optionally substituted 3-8-membered-heterocyclyl,optionally substituted 5-14-membered-heteroaryl, optionally substitutedC₆₋₁₀aryl, optionally substituted C₁₋₃₀alkyl, optionally substitutedC₂₋₃₀alkenyl, or optionally substituted C₂₋₃₀alkynyl.

In certain embodiments, B is hydrogen.

In certain embodiments, B is optionally substituted C₁₋₃₀alkyl. Incertain embodiments, B is optionally substituted C₂₋₃₀alkenyl. Incertain embodiments, B is optionally substituted C₂₋₃₀alkynyl.

In certain embodiments, B is optionally substituted C₃₋₇carbocyclyl,e.g., optionally substituted cyclohexyl. In certain embodiments, B isoptionally substituted 3-8-membered-heterocyclyl. In certainembodiments, B is optionally substituted 5-14-membered-heteroaryl. Incertain embodiments, B is optionally substituted C₆₋₁₀aryl. In certainembodiments, B is optionally substituted C₆aryl (i.e., phenyl). Incertain embodiments, B is optionally substituted C₁₀aryl (i.e.,napthyl).

For example, in certain embodiments, B is an optionally substitutedphenyl of the Formula (viii):

wherein:

Y is selected from the group consisting of optionally substitutedC₁₋₁₀alkyl, C₁₋₁₀perhaloalkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, halo, nitro, cyano, thiol,substituted thiol, hydroxyl, substituted hydroxyl, amino,monosubstituted amino, and disubstituted amino; and n is 0 or an integerof from 1 to 5, inclusive.

In certain embodiments, n is 0 or an integer from 1 to 3, inclusive.

In certain embodiments, n is 0 or an integer from 1 to 2, inclusive.

In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2.

In certain embodiments, n is 3.

For example, in certain embodiments, wherein n is 1, the group of theFormula (viii) is of the formula:

In certain embodiments, wherein n is 2, the group of the Formula (viii)is of the formula:

In certain embodiments, Y is halo, i.e. selected from fluoro, iodo,bromo, or chloro. In certain embodiments Y is chloro. In certainembodiments Y is fluoro.

In certain embodiments, Y is optionally substituted C₁₋₁₀alkyl orC₁₋₁₀perhaloalkyl.

In certain embodiments, Y is optionally substituted C₁₋₁₀alkyl. Incertain embodiments, Y is optionally substituted C₁₋₆alkyl. In certainembodiments, Y is optionally substituted C₁₋₄alkyl. In certainembodiments, Y is optionally substituted C₁₋₃alkyl. In certainembodiments, Y is optionally substituted C₁₋₂alkyl. In certainembodiments, Y is —CH₃, —CH₂F, or —CHF₂.

In certain embodiments, Y is C₁₋₁₀perhaloalkyl. In certain embodiments,Y is C₁₋₆perhaloalkyl. In certain embodiments, Y is C₁₋₄perhaloalkyl. Incertain embodiments, Y is C₁₋₃perhaloalkyl. In certain embodiments, Y isC₁₋₂perhaloalkyl. In certain embodiments, Y is —CF₃, —CF₂C₁, or —CFCl₂.

As generally defined above, Z is ═O, ═S, or ═NR_(Z), wherein R_(Z) isselected from hydrogen, an amino protecting group, —OH, substitutedhydroxyl, optionally substituted C₁₋₁₀alkyl, optionally substitutedC₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl, optionallysubstituted C₃₋₇carbocyclyl, optionally substituted3-8-membered-heterocyclyl, optionally substituted C₆₋₁₀aryl, oroptionally substituted 5-14-membered-heteroaryl, or Z represents twohydrogen atoms.

In certain embodiments, Z is ═O.

In certain embodiments, Z is ═S.

In certain embodiments, Z is ═NR_(Z), wherein R_(Z) is selected fromhydrogen, an amino protecting group, —OH, substituted hydroxyl,optionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, optionally substitutedC₃₋₇carbocyclyl, optionally substituted 3-8-membered-heterocyclyl,optionally substituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl. In certain embodiments, Z is ═NR_(Z) and R_(Z)is hydrogen.

In certain embodiments, Z represents two hydrogen atoms.

As generally defined above, X is —OR₄, —SR₄, or —N(R₄)₂, wherein eachinstance of R₄ is independently hydrogen, optionally substitutedC₁₋₃₀alkyl, optionally substituted C₂₋₃₀alkenyl, optionally substitutedC₂₋₃₀alkynyl, —C(═O)R₅, or —C(═O)OR₅, wherein R₅ is optionallysubstituted C₁₋₃₀alkyl, optionally substituted C₂₋₃₀alkenyl, oroptionally substituted C₂₋₃₀alkynyl, or two R₄ groups are joined to forman optionally substituted 3-8-membered-heterocyclyl or optionallysubstituted 5-14-membered-heteroaryl ring.

In certain embodiments, X is —OR₄. In certain embodiments, X is —OR₄,and R₄ is hydrogen. In certain embodiments, X is —OR₄, and R₄ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₄ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₄ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —OR₄, wherein R₄ is —C(═O)R₅, or —C(═O)OR₅.

In certain embodiments, X is —OR₄, and R₄ is —C(═O)R₅, and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl.

In certain embodiments, R₅ is optionally substituted C₁₋₁₀alkyl,optionally substituted C₂₋₁₀alkenyl, or optionally substitutedC₂₋₁₀alkynyl. In certain embodiments, R₅ is optionally substitutedC₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, or C₄₋₆alkyl. In certainembodiments, R₅ is optionally substituted C₂₋₆alkenyl, e.g.,C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certain embodiments, R₅ isoptionally substituted C₂₋₆alkynyl, e.g., C₂₋₃alkynyl, C₃₋₄alkynyl, orC₄₋₆alkynyl.

In certain embodiments, X is —OR₄, and R₄ is —C(═O)OR₅ and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl.

In certain embodiments, R₅ is optionally substituted C₁₋₁₀alkyl,optionally substituted C₂₋₁₀alkenyl, or optionally substitutedC₂₋₁₀alkynyl. In certain embodiments, R₅ is optionally substitutedC₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, or C₄₋₆alkyl. In certainembodiments, R₅ is optionally substituted C₂₋₆alkenyl, e.g.,C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certain embodiments, R₅ isoptionally substituted C₂₋₆alkynyl, e.g., C₂₋₃alkynyl, C₃₋₄alkynyl, orC₄₋₆alkynyl.

In certain embodiments, X is —SR₄. In certain embodiments, X is —SR₄,and R₄ is hydrogen. In certain embodiments, X is —SR₄, and R₄ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₄ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₄ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —SR₄, wherein R₄ is —C(═O)R₅, or —C(═O)OR₅.

In certain embodiments, X is —SR₄, and R₄ is —C(═O)R₅, and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₅ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —SR₄, and R₄ is —C(═O)OR₅ and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₅ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —N(R₄)₂. In certain embodiments, X is—N(R₄)₂ and at least one R₄ group is hydrogen. In certain embodiments, Xis —N(R₄)₂ and neither of the two R₄ groups are hydrogen. In certainembodiments, X is —N(R₄)₂ and at least one R₄ is optionally substitutedC₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl, or optionallysubstituted C₂₋₂₀alkynyl. In certain embodiments, X is —N(R₄)₂ and atleast one R₄ is optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₂₋₁₀alkenyl, or optionally substituted C₂₋₁₀alkynyl. Incertain embodiments, X is —N(R₄)₂ and at least one R₄ is optionallysubstituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, or C₄₋₆alkyl Incertain embodiments, X is —N(R₄)₂ and at least one R₄ is optionallysubstituted C₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl.In certain embodiments, X is —N(R₄)₂ and at least one R₄ is optionallysubstituted C₂₋₄alkynyl, e.g., C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.However, in certain embodiments, X is not —NH(iPr).

In certain embodiments, X is —N(R₄)₂ and at least one R₄ is —C(═O)R₅, or—C(═O)OR₅.

In certain embodiments, X is —N(R₄)₂ and at least one R₄ is —C(═O)R₅,and R₅ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, or optionally substituted C₂₋₂₀alkynyl. In certainembodiments, R₅ is optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₂₋₁₀alkenyl, or optionally substituted C₂₋₁₀alkynyl. Incertain embodiments, R₅ is optionally substituted C₁₋₆alkyl, e.g.,C₁₋₃alkyl, C₃₋₄-alkyl, or C₄₋₆alkyl. In certain embodiments, R₅ isoptionally substituted C₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, orC₄₋₆alkenyl. In certain embodiments, R₅ is optionally substitutedC₂₋₄alkynyl, e.g., C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —N(R₄)₂ and at least one R₄ is —C(═O)OR₅and R₅ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, or optionally substituted C₂₋₂₀alkynyl. In certainembodiments, R₅ is optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₂₋₁₀alkenyl, or optionally substituted C₂₋₁₀alkynyl. Incertain embodiments, R₅ is optionally substituted C₁₋₆alkyl, e.g.,C₁₋₃alkyl, C₃₋₄alkyl, or C₄₋₆alkyl. In certain embodiments, R₅ isoptionally substituted C₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, orC₄₋₆alkenyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkynyl, e.g., C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In other embodiments, X is —N(R₄)₂ and the two R₄ groups are joined toform an optionally substituted 3-8-membered-heterocyclyl or optionallysubstituted 5-14-membered-heteroaryl ring.

In certain embodiments, wherein X is —OR₄, —SR₄, or —N(R₄)₂, any one ofR₄ or R₅ is optionally substituted C₁₋₃₀alkyl (e.g., C₁₋₁₀alkyl,C₁₋₆alkyl, C₁₋₃alkyl, C₇₋₃₀alkyl, C₁₀₋₃₀alkyl, C₇₋₂₅alkyl, C₁₀₋₂₅alkyl,C₁₅₋₂₅alkyl). In certain embodiments, any one of R₄ or R₅ is optionallysubstituted C₂₋₃₀alkenyl (e.g., C₂₋₁₀alkenyl, C₂₋₆alkenyl, C₁₋₃alkenyl,C₇₋₃₀alkenyl, C₁₀₋₃₀alkenyl, C₇₋₂₅alkenyl, C₁₀₋₂₅alkenyl,C₁₅₋₂₅alkenyl). In certain embodiments, any one of R₄ or R₅ isoptionally substituted C₂₋₃₀alkynyl (e.g., C₂₋₁₀alkynyl, C₂₋₆alkynyl,C₁₋₃alkynyl, C₇₋₃₀alkynyl, C₁₀₋₃₀alkynyl, C₇₋₂₅alkynyl, C₁₀₋₂₅alkynyl,C₁₅₋₂₅alkynyl).

In any of the above embodiments, when R₄ or R₅ are defined as aC₇₋₃₀alkyl or C₇₋₃₀alkenyl groups, such groups may also be referred toas “lipid tails.” Lipid tails present in these lipid groups can besaturated and unsaturated, depending on whether or not the lipid tailcomprises double bonds. The lipid tail can also comprise differentlengths, often categorized as medium (i.e., with tails between 7-12carbons, e.g., C₇₋₁₂ alkyl or C₇₋₁₂ alkenyl), long (i.e., with tailsgreater than 12 carbons and up to 22 carbons, e.g., C₁₃₋₂₂ alkyl orC₁₃₋₂₂ alkenyl), or very long (i.e., with tails greater than 22 carbons,e.g., C₂₃₋₃₀ alkyl or C₂₃₋₃₀ alkenyl).

Exemplary unsaturated lipid tails include, but are not limited to:

Myristoleic —(CH₂)₇CH═CH(CH₂)₃CH₃,

Palmitoliec —(CH₂)₇CH═CH(CH₂)₅CH₃,

Sapienic —(CH₂)₄CH═CH(CH₂)₈CH₃,

Oleic —(CH₂)₇CH═CH(CH₂)₇CH₃,

Linoleic —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃,

α-Linolenic —(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃,

Arachinodonic —(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃,

Eicosapentaenoic —(CH₂)₃CH═CHCH₂CH═CHCH₂CHCHCHCH═CHCHCH₃,

Erucic —(CH₂)₁₁CH═CH(CH₂)₇CH₃, and

Docosahexaenoic—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH—CHCH₃.

Exemplary saturated lipid tails include, but are not limited to:

-   -   Lauric —(CH₂)₁₀CH₃,    -   Myristic —(CH₂)₁₂CH₃,    -   Palmitic —(CH₂)₁₄CH₃,    -   Stearic —(CH₂)₁₆CH₃,    -   Arachidic —(CH₂)₁₈CH₃,    -   Behenic —(CH₂)₂₀CH₃,    -   Lignoceric —(CH₂)₂₂CH₃, and    -   Cerotic —(CH₂)₂₄CH₃.

In certain embodiments of Formula (I), the compound is of Formula (I-a):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein;

-   -   each instance of        independently represents a single bond or a double bond which        can be in the cis or trans configuration;    -   each instance of R₃ and R₃′ is independently hydrogen, halogen,        —OH, substituted hydroxyl, or —O(CO)R₈, wherein R₈ is optionally        substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,        optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m        is 0 or an integer between 1-10, inclusive, and R₉ is optionally        substituted C₃₋₇carbocyclyl, optionally substituted C₆₋₁₀aryl,        or optionally substituted 5-14-membered-heteroaryl, or R₃ and        R₃′ are joined to form ═O;

Y is selected from the group consisting of optionally substitutedC₁₋₁₀alkyl, C₁₋₁₀perhaloalkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, halo, nitro, cyano, thiol,substituted thiol, hydroxyl, substituted hydroxyl, amino,monosubstituted amino, and disubstituted amino;

G is —O— or —S—;

y is 0, 1, or 2;

x is 0 or 1; and

n is 0 or an integer of from 1 to 5, inclusive.

In certain embodiments of Formula (I-a), wherein R₃′ is hydrogen, thecompound is of Formula (I-b):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments of Formula (I-a), wherein R₃ is hydrogen, thecompound is of Formula (I-c):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments of Formula (I-a), wherein G is —O—, provided is acompound of Formula (I-a1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-b), wherein G is —O—, the compoundis of Formula (I-b1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-c), wherein G is —O—, the compoundis of Formula (I-c1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-a), wherein G is —S—, provided is acompound of Formula (I-a2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein; wherein

, R₁, R₂, R₃, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-b), wherein G is —S—, the compoundis of Formula (I-b2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-c), wherein G is —S—, the compoundis of Formula (I-c2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments, the compound of Formula (I-a) has the followingstereochemistry, also referred to herein as a compound of Formula (I-d):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, Z, Y, G, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d), wherein R₃′ is hydrogen, thecompound is of Formula (I-e):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d), wherein R₃ is hydrogen, thecompound is of Formula (I-f):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′ Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments of Formula (I-d), wherein G is —O—, the compoundis of Formula (I-dl):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, Z, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-e), wherein G is —O—, the compoundis of Formula (I-e1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-f), wherein G is —O—, the compoundis of Formula (I-f1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d), wherein G is —S—, the compoundis of Formula (I-d2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, Z, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-e), wherein G is —S—, the compoundis of Formula (I-e2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-f), wherein G is —S—, the compoundis of Formula (I-f2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments, Z is ═O. In certain embodiments, each

represents a single bond. In certain embodiments, each endocyclic

represents a single bond. In certain embodiments at least one exocyclic

represents a cis-double bond. In certain embodiments, each instance ofR₁ and R₂ is —OH. In certain embodiments, each instance of R₁ and R₂ is—O(CO)R₆. In certain embodiments, one of R₁ and R₂ is —OH, and the otherone is —O(CO)R₆. In certain embodiments, one of R₃ and R₃′ is —O(CO)R₈,and the other is hydrogen. In certain embodiments, R₁ is —OH, R₂ is—O(CO)R₆, one of R₃ and R₃′ is —OH, and the other is hydrogen. Incertain embodiments, R₂ is —OH, R₁ is —O(CO)R₆, one of R₃ and R₃′ is—OH, and the other is hydrogen. In certain embodiments, each of R₁ andR₂ is —OH, and one of R₃ and R₃′ is —O(CO)R₈, and the other is hydrogen.In certain embodiments, each instance of R₁ and R₂ is —O(CO)R₆, and oneof R₃ and R₃′ is —O(CO)R₈, and the other is hydrogen. In certainembodiments, —O(CO)R₆ and —O(CO)R₈ attached to the compound are the samegroup. In certain embodiments, —O(CO)R₆ and —O(CO)R₈ attached to thecompound are different groups.

In certain embodiments of Formula (I-d), wherein Z is ═O, eachendocyclic

represents a single bond, and at least one exocyclic

represents a cis-double bond, provided is a compound of Formula (I-d3)having the following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-e), wherein Z is ═O, eachendocyclic

represents a single bond, and at least one exocyclic

represents a cis-double bond, provided is a compound of Formula (I-e3)having the following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, G, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-f), wherein Z is ═O, eachendocyclic

represents a single bond, and at least one exocyclic

represents a cis-double bond, provided is a compound of Formula (I-f3)having the following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, G, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d3), wherein R₁ is —OH and R₂ is—O(CO)R₆, or wherein R₂ is —OH and R₁ is —O(CO)R₆, or wherein both R₁and R₂ are —O(CO)R₆, provided is a compound of Formula (I-d4), (I-d5),and (I-d6) having the following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₆, R₃, R₃′, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d3), wherein R₃ is —O(CO)R₈ or R₃′is —O(CO)R₈, provided is a compound of Formula (I-d7) and (I-d8) havingthe following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, R₈, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d3), wherein R₁ and R₂ are each —OHand R₃ is —O(CO)R₈, or wherein R₁ and R₂ are each —OH and R₃′ is—O(CO)R₈, provided is a compound of Formula (I-d9) and (I-d10) havingthe following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₃, R₃′, R₈, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-e3), wherein R₁ is —OH and R₂ is—O(CO)R₆, or wherein R₂ is —OH and R₁ is —O(CO)R₆, or wherein both R₁and R₂ are —O(CO)R₆, and R₃′ is hydrogen and R₃ is —OH, provided is acompound of Formula (I-d11), (I-d12), and (I-d13) having the followingstereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₆, R₃, R₃′, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d8), wherein each of R₁ and R₂ are—O(CO)R₆ and R₃′ is hydrogen, provided is a compound of Formula (I-d14)having the following stereochemistry:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₆, R₈, G, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d2), wherein Z is ═O, each instanceof R₁ and R₂ is —OH, and each

represents a single bond, provided is a compound of Formula (I-g):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein X, Y, R₃, R₃′, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d1), wherein each instance of R₁and R₂ is —OH, and Z is ═O, provided is a compound of Formula (I-h):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₃, R₃′, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-h), wherein R₃′ is hydrogen,provided is a compound of Formula (I-i):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₃, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-i), wherein R₃ is —OH, provided isa compound of Formula (I-j):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-h), wherein R₃ is F and R₃′ is F,provided is a compound of Formula (I-k):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-i), wherein R₃ is —O(CO)R₈,provided is a compound of Formula (I-j):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₈, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I), the compound of Formula (I-l):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein;

each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration;

each instance of R₃ and R₃′ is independently hydrogen, halogen, —OH,substituted hydroxyl, or —O(CO)R₈, wherein R₈ is optionally substitutedC₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substitutedC₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 or an integer between 1-10,inclusive, and R₉ is optionally substituted C₃₋₇carbocyclyl, optionallysubstituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl, or R₃ and R₃′ are joined to form ═O;

Y is selected from the group consisting of optionally substitutedC₁₋₁₀alkyl, C₁₋₁₀perhaloalkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, halo, nitro, cyano, thiol,substituted thiol, hydroxyl, substituted hydroxyl, amino,monosubstituted amino, and disubstituted amino;

G is —O— or —S—;

y is 0, 1, or 2;

x is 0 or 1; and

n is 0 or an integer of from 1 to 5, inclusive.

In certain embodiments of Formula (I-l), wherein Z is ═O, and R₁ and R₂are each —OH, provided is a compound of Formula (I-m):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein.

In certain embodiments of Formula (I-m), wherein R₃′ is hydrogen, y is 2and x is 0, provided is a compound of Formula (I-n):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein.

As generally defined above, in certain embodiments, provided is acompound of Formula (II):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof, wherein A, B, X, Z, L, and R₁ are as defined herein are asdefined herein.

In certain embodiments, L is a group of the formula

wherein

represents a single bond.

In certain embodiments, L is a group of the formula

wherein

represents a double bond which can be in the cis or trans configuration.In certain embodiments, the double bond is in the cis configuration. Incertain embodiments, the double bond is in the trans configuration

In certain embodiments, L is a group of the formula

wherein

represents a single bond.

In certain embodiments, L is a group of the formula

wherein

represents a double bond which can be in the cis or trans configuration.In certain embodiments, the double bond is in the cis configuration. Incertain embodiments, the double bond is in the trans configuration

In certain embodiments of Formula (II), the compound of Formula (II-a):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof, wherein

, R₁, Z, X, Y, G, R₃, R₃′, y, x, and n are as defined herein.

In certain embodiments of Formula (II-a), wherein R₃′ is hydrogen, thecompound is of Formula (II-b):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₃, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments of Formula (II-a), wherein R₃ is hydrogen, thecompound is of Formula (II-c):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments of Formula (II-a), wherein G is —O—, provided isa compound of Formula (II-a1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein; wherein

R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments, Z is ═O.

In certain embodiments at least one exocyclic

represents a cis-double bond.

For example, in certain embodiments of Formula (II-a1), wherein Z is ═O,provided is a compound of Formula (II-d):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

R₁, R₃, R₃′, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (II-d), wherein R₁ is OH, R₃′ ishydrogen, R₃ is —OH, y is 0, and x is 1, provided is a compound ofFormula (II-e):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, Y, X, and n are as defined herein.

Exemplary compounds of Formula (I) include, but are not limited to:

referred to herein as Prostagladin F2α;

also referred to herein as bimatoprost;

also referred to herein as bimatoprost isopropyl ester;

also referred to herein as bimatoprost free acid;

also referred to herein as travoprost;

also referred to herein as travoprost free acid or fluprostenol;

also referred to herein as latanoprost;

also referred to herein as latanoprost free acid;

also referred to herein as tafluprost;

also referred to herein as tafluprost free acid or AFP-172;

also referred to herein as CAY10509;

also referred to herein as CAY10509 free acid;and 9-, 11-, and/or 15-ester derivatives (e.g., prodrugs) of the above,e.g., of formula:

wherein:

R₁ is —O(CO)R₆ and R₂ is —OH, or

R₁ is —OH, R₂ is —O(CO)R₆, or

R₁ is —OH, R₂ is —OH, and R₃ is —O(CO)R₈, or

R₁ is —OH, R₂ is —O(CO)R₆, and R₃ is —OH, or

R₁ is —O(CO)R₆, R₂ is —O(CO)R₆, and R₃ is —OH, or

R₁ is —O(CO)R₆, R₂ is —OH, and R₃ is —O(CO)R₈, or

R₁ is —OH, R₂ is —O(CO)R₆, and R₃ is —O(CO)R₈, or

R₁ is —O(CO)R₆, R₂ is —O(CO)R₆, and R₃ is —O(CO)R₈, wherein R₆ and R₈are as defined herein, and pharmaceutically acceptable salts, hydrates,solvates, stereoisomers, polymorphs, tautomers, isotopically enrichedderivatives, and prodrugs thereof. In certain embodiments, R₈ is—(CH₂)_(q)CH₃ wherein q is 0, 1, 2, 3, 4, 5, or 6, —CH(CH₃)₂,—CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃. In certain embodiments, R₆ is—(CH₂)_(r)CH₃, wherein r is 0, 1, 2, 3, 4, 5, or 6, —CH(CH₃)₂,—CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃.

In certain embodiments, the compound of Formula (I) is selected from thegroup consisting of latanoprost, latanoprost free acid, tafluprost,tafluprost free acid, travoprost, fluprostenol, bimatoprost, bimatoprostfree acid, and pharmaceutically acceptable salts, hydrates, solvates,stereoisomers, polymorphs, tautomers, isotopically enriched derivatives,and prodrugs thereof. In certain embodiments, the compound of Formula(I) is selected from the group consisting of latanoprost, latanoprostfree acid, tafluprost, tafluprost free acid, and pharmaceuticallyacceptable salts, hydrates, solvates, stereoisomers, polymorphs,tautomers, isotopically enriched derivatives, and prodrugs thereof. Incertain embodiments, the compound of Formula (I) is selected from thegroup consisting of latanoprost and pharmaceutically acceptablehydrates, solvates, stereoisomers, polymorphs, tautomers, isotopicallyenriched derivatives, and prodrugs thereof. In certain embodiments, thecompound of Formula (I) is selected from the group consisting oflatanoprost free acid and pharmaceutically acceptable salts, hydrates,solvates, stereoisomers, polymorphs, tautomers, isotopically enrichedderivatives, and prodrugs thereof. In certain embodiments, the compoundof Formula (I) is latanoprost. In certain embodiments, the compound ofFormula (I) is selected from the group consisting of tafluprost andpharmaceutically acceptable hydrates, solvates, stereoisomers,polymorphs, tautomers, isotopically enriched derivatives, and prodrugsthereof. In certain embodiments, the compound of Formula (I) is selectedfrom the group consisting of tafluprost free acid and pharmaceuticallyacceptable salts, hydrates, solvates, stereoisomers, polymorphs,tautomers, isotopically enriched derivatives, and prodrugs thereof. Incertain embodiments, the compound of Formula (I) is tafluprost.

Exemplary compounds of Formula (II) include, but are not limited to,

also referred to as AL-12182;

also referred to as AL-12182 free acid;and ester derivatives (e.g., prodrugs) of the above, e.g., of formula:

wherein:

R₁ is —OH and R₃ is —O(CO)R₈, or

R₁ is —O(CO)R₆, and R₃ is —OH, or

R₁ is —O(CO)R₆, and R₃ is —O(CO)R₈,

wherein R₆ and R₈ are as defined herein, and pharmaceutically acceptablesalts, hydrates, solvates, stereoisomers, polymorphs, tautomers,isotopically enriched derivatives, and prodrugs thereof. In certainembodiments, R₈ is —(CH₂)_(q)CH₃, wherein q is 0, 1, 2, 3, 4, 5, or 6,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃. In certainembodiments, R₆ is —(CH₂)_(r)CH₃, wherein r is 0, 1, 2, 3, 4, 5, or 6,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, or —C(CH₃)₃.

In certain embodiments, the compound of Formula (I) or (II) is a prodrugof any one of the compounds described herein. Exemplary prodrugs includeesters, amides, and/or thioamides of the parent free acid, and compoundswherein a hydroxyl group on the parent compound (e.g., a pentacyclichydroxyl group R₁ and/or R₂ or the hydroxyl group at the R₃ and/or R₃′position) is esterified, e.g., 9-, 11-, and/or 15-ester derivatives asdescribed herein, e.g., wherein the ester at said position is a C₁₋₆ester, e.g., 9-propionyl bimatoprost, 11-propionyl bimatoprost,15-propionyl bimatoprost, 9-butyryl bimatoprost, 11-butyryl bimatoprost,15-butyryl bimatoprost, and the like.

Compositions and Formulations

In certain embodiments, the present invention provides compositions fortopical administration of a composition comprising a PFPRA compound, asdescribed herein, and a fatty acid ester (e.g., isopropyl myristate).Compositions, as used herein, encompass pharmaceutical compositions aswell as cosmetic compositions.

In certain embodiments, the composition comprises a PFPRA compound,fatty acid ester (e.g., isopropyl myristate), and an ointment base. Insome embodiments, the composition further comprises an organic alcohol,e.g., methanol, ethanol, propanol, isopropanol, 1,3-butanediol, ethyleneglycol, or propylene glycol. In certain embodiments, the organic alcoholis propylene glycol. In certain embodiments, the composition compriseslatanoprost, isopropyl myristate, and an ointment base. In certainembodiments, the composition comprises tafluoprost, isopropyl myristate,and an ointment base. In certain embodiments, the composition consistsessentially of the above-recited components. In certain embodiments, thecomposition is not irritating to the skin. In certain embodiments, thecomposition is sterile, endotoxin-free or essentially endotoxin-free,ophthalmic, and/or ophthalmically compatible.

Kalayoglu (PCT/US2012/021692; WO2012/099942) teaches certainformulations for systemic (transdermal) delivery of a PFPRA to thebloodstream. These include two emulsions (Lipoderm or pluronic lecithinorganogel). Emulsions are challenging to manufacture and susceptible tophase separation; e.g., for example, pluronic lecithin organogel isprone to phase separation at temperatures of about 5° C. or below. Thus,in some embodiments, the composition is a non-emulsion, i.e., is not anemulsion. In some embodiments, the composition in a non-emulsioncomprising a PFPRA compound, fatty acid ester (e.g., isopropylmyristate), and an ointment base. In some embodiments, the compositionis a non-emulsion comprising a PFPRA compound, fatty acid ester (e.g.,isopropyl myristate), an organic alcohol, and an ointment base.

In some embodiments, the PFPRA compound is a compound of Formula (I) or(II), or a pharmaceutically acceptable salt, hydrate, solvate,stereoisomer, polymorph, tautomer, isotopically enriched derivative, orprodrug thereof. In some embodiments, the PFPRA compound is latanoprost,tafluprost, travoprost, or bimatoprost, or a pharmaceutically acceptablesalt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopicallyenriched derivative, or prodrug thereof. In certain embodiments, thePFPRA compound is selected from the group consisting of latanoprost,latanoprost free acid, tafluprost, tafluprost free acid, andpharmaceutically acceptable salts, hydrates, solvates, stereoisomers,polymorphs, tautomers, isotopically enriched derivatives, and prodrugsthereof. In certain embodiments, the PFPRA compound is selected from thegroup consisting of latanoprost and pharmaceutically acceptablehydrates, solvates, stereoisomers, polymorphs, tautomers, isotopicallyenriched derivatives, and prodrugs thereof. In certain embodiments, thePFPRA compound is selected from the group consisting of latanoprost freeacid and pharmaceutically acceptable salts, hydrates, solvates,stereoisomers, polymorphs, tautomers, isotopically enriched derivatives,and prodrugs thereof. In certain embodiments, the PFPRA compound isselected from the group consisting of tafluprost and pharmaceuticallyacceptable hydrates, solvates, stereoisomers, polymorphs, tautomers,isotopically enriched derivatives, and prodrugs thereof. In certainembodiments, the PFPRA compound is selected from the group consisting oftafluprost free acid and pharmaceutically acceptable salts, hydrates,solvates, stereoisomers, polymorphs, tautomers, isotopically enrichedderivatives, and prodrugs thereof. In certain embodiments, the PFPRAcompound is latanoprost. In certain embodiments, the PFPRA compound istafluprost. In certain embodiments, the PFPRA compound hydrolyzes to anactive metabolite (e.g., the free acid of latanoprost, tafluprost,travoprost, or bimatoprost) upon administration to the skin.

In some embodiments, the final concentration of the PFPRA compoundprovided in the composition is between about 0.0001 percent and about 1percent (by weight). In some embodiments, the final concentration isbetween about 0.001 percent and about 1 percent, 0.001 and about 0.003percent, about 0.001 and about 0.01 percent, about 0.003 and about 0.01percent, about 0.01 and about 0.03 percent, about 0.01 and about 0.1percent, about 0.05 and about 5 percent, about 0.03 and about 0.1percent, about 0.1 and about 0.3 percent, about 0.1 and about 1 percent,or about 0.3 and about 1 percent (by weight), inclusive. Thesepercentages are expressed by weight of the total weight of thecomposition.

In some embodiments, the PFPRA compound is latanoprost and the finalconcentration of latanoprost is between about 0.001 percent and about 1percent, 0.001 and about 0.003 percent, about 0.001 and about 0.01percent, about 0.003 and about 0.01 percent, about 0.01 and about 0.03percent, about 0.01 and about 0.1 percent, about 0.05 and about 5percent, about 0.03 and about 0.1 percent, about 0.1 and about 0.3percent, about 0.1 and about 1 percent, about 0.05 and about 5 percent,or about 0.3 and about 1 percent (by weight), inclusive.

In some embodiments, the PFPRA compound is tafluprost and the finalconcentration of tafluprost is between about 0.001 percent and about 1percent, 0.001 and about 0.003 percent, about 0.001 and about 0.01percent, about 0.003 and about 0.01 percent, about 0.01 and about 0.03percent, about 0.01 and about 0.1 percent, about 0.05 and about 5percent, about 0.03 and about 0.1 percent, about 0.1 and about 0.3percent, about 0.1 and about 1 percent, about 0.05 and about 5 percent,or about 0.3 and about 1 percent (by weight), inclusive. Thesepercentages are expressed by weight of the total weight of thecomposition.

In some embodiments, the final concentration of the fatty acid ester(e.g., isopropyl myristate) is between about 1 percent to about 20percent by weight, inclusive. In some embodiments, the finalconcentration is between about 5 and about 15 percent, about 1 and about10 percent, about 1 and about 2 percent, about 1 and about 3 percent,about 2 and about 4 percent, about 3 and about 5 percent, about 3 andabout 7 percent, about 4 and about 6 percent, about 5 and about 7percent, about 6 and about 8 percent, about 7 and about 10 percent,about 10 and about 20 percent, about 10 and about 15 percent, or about15 and about 20 percent, inclusive. In certain embodiments, the finalconcentration of the fatty acid ester (e.g., isopropyl myristate) is 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20percent by weight. These percentages are expressed by weight of thetotal weight of the composition.

In some embodiments, the PFPRA compound is latanoprost; the finalconcentration of latanoprost is between about 0.001 percent and about 1percent, 0.001 and about 0.003 percent, about 0.001 and about 0.01percent, about 0.003 and about 0.01 percent, about 0.01 and about 0.03percent, about 0.01 and about 0.1 percent, about 0.03 and about 0.1percent, about 0.1 and about 0.3 percent, about 0.1 and about 1 percent,about 0.05 and about 5 percent, or about 0.3 and about 1 percent (byweight), inclusive; and the final concentration of fatty acid ester(e.g., isopropyl myristate) is between about 5 and about 15 percent,about 1 and about 10 percent, about 1 and about 2 percent, about 1 andabout 3 percent, about 2 and about 4 percent, about 3 and about 5percent, about 3 and about 7 percent, about 4 and about 6 percent, about5 and about 7 percent, about 6 and about 8 percent, about 7 and about 10percent, about 10 and about 20 percent, about 10 and about 15 percent,or about 15 and about 20 percent, by weight, inclusive. Thesepercentages are expressed by weight of the total weight of thecomposition.

In some embodiments, the PFPRA compound is tafluprost; the finalconcentration of tafluprost is between about 0.001 percent and about 1percent, 0.001 and about 0.003 percent, about 0.001 and about 0.01percent, about 0.003 and about 0.01 percent, about 0.01 and about 0.03percent, about 0.01 and about 0.1 percent, about 0.05 and about 5percent, about 0.03 and about 0.1 percent, about 0.1 and about 0.3percent, about 0.1 and about 1 percent, or about 0.3 and about 1 percent(by weight), inclusive; and the final concentration of fatty acid ester(e.g., isopropyl myristate) is between about 5 and about 15 percent,about 1 and about 10 percent, about 1 and about 2 percent, about 1 andabout 3 percent, about 2 and about 4 percent, about 3 and about 5percent, about 3 and about 7 percent, about 4 and about 6 percent, about5 and about 7 percent, about 6 and about 8 percent, about 7 and about 10percent, about 10 and about 20 percent, about 10 and about 15 percent,or about 15 and about 20 percent, by weight, inclusive. Thesepercentages are expressed by weight of the total weight of thecomposition.

In some embodiments, the composition comprises an ointment base, e.g., ahydrocarbon base. In some embodiments, the hydrocarbon base is selectedfrom the group consisting of white wax, yellow wax, hard paraffin wax,petroleum jelly, and cetyl esters wax. In some embodiments, the finalconcentration of ointment base is between about 50 percent and about 99percent by weight. In some embodiments, the final concentration ofointment base is between about 50 percent and 60 percent, 50 percent andabout 70 percent, about 60 percent and about 70 percent, about 60percent and about 80 percent, about 70 percent and about 80 percent,about 70 percent and about 90 percent, about 70 percent and about 99percent, about 80 percent and about 90 percent, about 85 percent andabout 95 percent, about 90 percent and about 95 percent, about 90percent and about 99 percent, and about 95 percent and about 99 percent,inclusive. In some embodiments, the ointment base is petroleum jelly,and the final concentration of petroleum jelly is between about 50percent and about 99 percent by weight, inclusive. In some embodiments,the final concentration of petroleum jelly is between about 50 percentand 60 percent, 50 percent and about 70 percent, about 60 percent andabout 70 percent, about 60 percent and about 80 percent, about 70percent and about 80 percent, about 70 percent and about 90 percent,about 70 percent and about 99 percent, about 80 percent and about 90percent, about 85 percent and about 95 percent, about 90 percent andabout 95 percent, about 90 percent and about 99 percent, and about 95percent and about 99 percent, inclusive.

In some embodiments, the PFPRA compound is latanoprost; the finalconcentration of latanoprost is between about 0.001 percent and about 1percent, 0.001 and about 0.003 percent, about 0.001 and about 0.01percent, about 0.003 and about 0.01 percent, about 0.01 and about 0.03percent, about 0.01 and about 0.1 percent, about 0.05 and about 5percent, about 0.03 and about 0.1 percent, about 0.1 and about 0.3percent, about 0.1 and about 1 percent, or about 0.3 and about 1 percent(by weight), inclusive; the final concentration of fatty acid ester(e.g., isopropyl myristate) is between about 5 and about 15 percent,about 1 and about 10 percent, about 1 and about 2 percent, about 1 andabout 3 percent, about 2 and about 4 percent, about 3 and about 5percent, about 3 and about 7 percent, about 4 and about 6 percent, about5 and about 7 percent, about 6 and about 8 percent, about 7 and about 10percent, about 10 and about 20 percent, about 10 and about 15 percent,or about 15 and about 20 percent, by weight, inclusive; and the finalconcentration of the ointment base (e.g., petroleum jelly) is betweenabout 50 percent and 60 percent, 50 percent and about 70 percent, about60 percent and about 70 percent, about 60 percent and about 80 percent,about 70 percent and about 80 percent, about 70 percent and about 90percent, about 70 percent and about 99 percent, about 80 percent andabout 90 percent, about 85 percent and about 95 percent, about 90percent and about 95 percent, about 90 percent and about 99 percent, andabout 95 percent and about 99 percent, inclusive. These percentages areexpressed by weight of the total weight of the composition.

In some embodiments, the PFPRA compound is tafluprost; the finalconcentration of tafluprost is between about 0.001 percent and about 1percent, 0.001 and about 0.003 percent, about 0.001 and about 0.01percent, about 0.003 and about 0.01 percent, about 0.01 and about 0.03percent, about 0.01 and about 0.1 percent, about 0.03 and about 0.1percent, about 0.1 and about 0.3 percent, about 0.1 and about 1 percent,about 0.05 and about 5 percent, or about 0.3 and about 1 percent (byweight), inclusive; and the final concentration of fatty acid ester(e.g., isopropyl myristate) is between about 5 and about 15 percent,about 1 and about 10 percent, about 1 and about 2 percent, about 1 andabout 3 percent, about 2 and about 4 percent, about 3 and about 5percent, about 3 and about 7 percent, about 4 and about 6 percent, about5 and about 7 percent, about 6 and about 8 percent, about 7 and about 10percent, about 10 and about 20 percent, about 10 and about 15 percent,or about 15 and about 20 percent, by weight, inclusive; and the finalconcentration of the ointment base (e.g., petroleum jelly) is betweenabout 50 percent and 60 percent, 50 percent and about 70 percent, about60 percent and about 70 percent, about 60 percent and about 80 percent,about 70 percent and about 80 percent, about 70 percent and about 90percent, about 70 percent and about 99 percent, about 80 percent andabout 90 percent, about 85 percent and about 95 percent, about 90percent and about 95 percent, about 90 percent and about 99 percent, andabout 95 percent and about 99 percent, inclusive. These percentages areexpressed by weight of the total weight of the composition.

In some embodiments, the composition further comprises an organicalcohol (e.g., propylene glycol). In some embodiments, the finalconcentration of propylene glycol is between about 5 percent and about50 percent by weight, inclusive. In some embodiments, the finalconcentration of the organic alcohol (e.g., propylene glycol) is betweenabout 5 percent and 10 percent, about 5 percent and about 15 percent,about 5 percent and about 20 percent, about 10 percent and about 15percent, about 10 percent and about 20 percent, about 15 percent andabout 20 percent, about 15 percent and about 25 percent, about 20percent and about 25 percent, about 20 percent and 30 percent about 25percent and about 30 percent, about 25 percent and about 35 percent,about 30 percent and about 35 percent, about 30 percent and about 40percent, about 35 percent and about 40 percent, about 35 percent andabout 45 percent, about 40 percent and about 50 percent, about 40percent and about 45 percent, or about 45 percent and about 50 percent,inclusive.

In some embodiments, the PFPRA compound is latanoprost; the finalconcentration of latanoprost is between about 0.001 percent and about 1percent, 0.001 and about 0.003 percent, about 0.001 and about 0.01percent, about 0.003 and about 0.01 percent, about 0.01 and about 0.03percent, about 0.01 and about 0.1 percent, about 0.05 and about 5percent, about 0.03 and about 0.1 percent, about 0.1 and about 0.3percent, about 0.1 and about 1 percent, or about 0.3 and about 1 percent(by weight), inclusive; and the final concentration of fatty acid ester(e.g., isopropyl myristate) is between about 5 and about 15 percent,about 1 and about 10 percent, about 1 and about 2 percent, about 1 andabout 3 percent, about 2 and about 4 percent, about 3 and about 5percent, about 3 and about 7 percent, about 4 and about 6 percent, about5 and about 7 percent, about 6 and about 8 percent, about 7 and about 10percent, about 10 and about 20 percent, about 10 and about 15 percent,or about 15 and about 20 percent, by weight, inclusive; and the finalconcentration of the organic alcohol (e.g., propylene glycol) is betweenabout 5 percent and 10 percent, about 5 percent and about 15 percent,about 5 percent and about 20 percent, about 10 percent and about 15percent, about 10 percent and about 20 percent, about 15 percent andabout 20 percent, about 15 percent and about 25 percent, about 20percent and about 25 percent, about 20 percent and 30 percent about 25percent and about 30 percent, about 25 percent and about 35 percent,about 30 percent and about 35 percent, about 30 percent and about 40percent, about 35 percent and about 40 percent, about 35 percent andabout 45 percent, about 40 percent and about 50 percent, about 40percent and about 45 percent, or about 45 percent and about 50 percent,inclusive. These percentages are expressed by weight of the total weightof the composition.

In some embodiments, the PFPRA compound is tafluprost; the finalconcentration of tafluprost is between about 0.001 percent and about 1percent, 0.001 and about 0.003 percent, about 0.001 and about 0.01percent, about 0.003 and about 0.01 percent, about 0.01 and about 0.03percent, about 0.01 and about 0.1 percent, about 0.03 and about 0.1percent, about 0.1 and about 0.3 percent, about 0.1 and about 1 percent,about 0.05 and about 5 percent, or about 0.3 and about 1 percent (byweight), inclusive; and the final concentration of fatty acid ester(e.g., isopropyl myristate) is between about 5 and about 15 percent,about 1 and about 10 percent, about 1 and about 2 percent, about 1 andabout 3 percent, about 2 and about 4 percent, about 3 and about 5percent, about 3 and about 7 percent, about 4 and about 6 percent, about5 and about 7 percent, about 6 and about 8 percent, about 7 and about 10percent, about 10 and about 20 percent, about 10 and about 15 percent,or about 15 and about 20 percent, by weight, inclusive; and the finalconcentration of the organic alcohol (e.g., propylene glycol) is betweenabout 5 percent and 10 percent, about 5 percent and about 15 percent,about 5 percent and about 20 percent, about 10 percent and about 15percent, about 10 percent and about 20 percent, about 15 percent andabout 20 percent, about 15 percent and about 25 percent, about 20percent and about 25 percent, about 20 percent and 30 percent about 25percent and about 30 percent, about 25 percent and about 35 percent,about 30 percent and about 35 percent, about 30 percent and about 40percent, about 35 percent and about 40 percent, about 35 percent andabout 45 percent, about 40 percent and about 50 percent, about 40percent and about 45 percent, or about 45 percent and about 50 percent,inclusive. These percentages are expressed by weight of the total weightof the composition.

In some embodiments, the PFPRA compound is latanoprost; the finalconcentration of latanoprost is between about 0.001 percent and about 1percent, 0.001 and about 0.003 percent, about 0.001 and about 0.01percent, about 0.003 and about 0.01 percent, about 0.01 and about 0.03percent, about 0.01 and about 0.1 percent, about 0.05 and about 5percent, about 0.03 and about 0.1 percent, about 0.1 and about 0.3percent, about 0.1 and about 1 percent, or about 0.3 and about 1 percent(by weight), inclusive; and the final concentration of fatty acid ester(e.g., isopropyl myristate) is between about 5 and about 15 percent,about 1 and about 10 percent, about 1 and about 2 percent, about 1 andabout 3 percent, about 2 and about 4 percent, about 3 and about 5percent, about 3 and about 7 percent, about 4 and about 6 percent, about5 and about 7 percent, about 6 and about 8 percent, about 7 and about 10percent, about 10 and about 20 percent, about 10 and about 15 percent,or about 15 and about 20 percent, by weight, inclusive; the finalconcentration of the organic alcohol (e.g., propylene glycol) is betweenabout 5 percent and 10 percent, about 5 percent and about 15 percent,about 5 percent and about 20 percent, about 10 percent and about 15percent, about 10 percent and about 20 percent, about 15 percent andabout 20 percent, about 15 percent and about 25 percent, about 20percent and about 25 percent, about 20 percent and 30 percent about 25percent and about 30 percent, about 25 percent and about 35 percent,about 30 percent and about 35 percent, about 30 percent and about 40percent, about 35 percent and about 40 percent, about 35 percent andabout 45 percent, about 40 percent and about 50 percent, about 40percent and about 45 percent, or about 45 percent and about 50 percent,inclusive; and the final concentration of the ointment base (e.g.,petroleum jelly) is between about 50 percent and 60 percent, 50 percentand about 70 percent, about 60 percent and about 70 percent, about 60percent and about 80 percent, about 70 percent and about 80 percent,about 70 percent and about 90 percent, about 70 percent and about 99percent, about 80 percent and about 90 percent, about 85 percent andabout 95 percent, about 90 percent and about 95 percent, about 90percent and about 99 percent, and about 95 percent and about 99 percent,inclusive. These percentages are expressed by weight of the total weightof the composition.

In some embodiments, the PFPRA compound is tafluprost; the finalconcentration of tafluprost is between about 0.001 percent and about 1percent, 0.001 and about 0.003 percent, about 0.001 and about 0.01percent, about 0.003 and about 0.01 percent, about 0.01 and about 0.03percent, about 0.01 and about 0.1 percent, about 0.05 and about 5percent, about 0.03 and about 0.1 percent, about 0.1 and about 0.3percent, about 0.1 and about 1 percent, or about 0.3 and about 1 percent(by weight), inclusive; and the final concentration of fatty acid ester(e.g., isopropyl myristate) is between about 5 and about 15 percent,about 1 and about 10 percent, about 1 and about 2 percent, about 1 andabout 3 percent, about 2 and about 4 percent, about 3 and about 5percent, about 3 and about 7 percent, about 4 and about 6 percent, about5 and about 7 percent, about 6 and about 8 percent, about 7 and about 10percent, about 10 and about 20 percent, about 10 and about 15 percent,or about 15 and about 20 percent, by weight, inclusive; the finalconcentration of the organic alcohol (e.g., propylene glycol) is betweenabout 5 percent and 10 percent, about 5 percent and about 15 percent,about 5 percent and about 20 percent, about 10 percent and about 15percent, about 10 percent and about 20 percent, about 15 percent andabout 20 percent, about 15 percent and about 25 percent, about 20percent and about 25 percent, about 20 percent and 30 percent about 25percent and about 30 percent, about 25 percent and about 35 percent,about 30 percent and about 35 percent, about 30 percent and about 40percent, about 35 percent and about 40 percent, about 35 percent andabout 45 percent, about 40 percent and about 50 percent, about 40percent and about 45 percent, or about 45 percent and about 50 percent,inclusive; and the final concentration of the ointment base (e.g.,petroleum jelly) is between about 50 percent and 60 percent, 50 percentand about 70 percent, about 60 percent and about 70 percent, about 60percent and about 80 percent, about 70 percent and about 80 percent,about 70 percent and about 90 percent, about 70 percent and about 99percent, about 80 percent and about 90 percent, about 85 percent andabout 95 percent, about 90 percent and about 95 percent, about 90percent and about 99 percent, and about 95 percent and about 99 percent,inclusive. These percentages are expressed by weight of the total weightof the composition.

In certain embodiments, the composition may further comprise otherpharmaceutically acceptable excipients including, but not limited to,solvents, diluents or other liquid vehicles, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, lubricants and the like. General considerationsin the formulation and/or manufacture of topical compositions can befound, for example, in Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), andRemington: The Science and Practice of Pharmacy, 21^(st) Edition(Lippincott Williams & Wilkins, 2005).

In some embodiments, the composition is sterile. Generally, methods ofmanufacturing a sterile composition include gamma irradiation, heat(e.g., autoclave or dry heat), and microfiltration (e.g., with a 0.2micron filter); however, some of these methods can be unsuitable forcertain compositions. For example, gamma irradiation or heat can causedegradation of the PFPRA compound; oleaginous bases such as petroleumjelly are not amenable to autoclave sterilization; and some excipientsmay be incompatible or poorly compatible with a 0.2 micron filter.

Compositions can be prepared, packaged, and/or sold in bulk, as a singleunit dose, and/or as a plurality of single unit doses. As used herein, a“unit dose” is discrete amount of the composition comprising apredetermined amount of the PFPRA compound. The amount of the PFPRAcompound is generally equal to the dosage of the PFPRA compound whichwould be administered to a subject and/or a convenient fraction of sucha dosage such as, for example, one-half or one-third of such a dosage.

Relative amounts of the PFPRA compound, the pharmaceutically acceptableexcipient, and/or any additional ingredients in a composition will vary,depending upon the identity, size, and/or condition of the subjecttreated and further depending upon the route by which the composition isto be administered.

Other Features of Compositions

Pharmaceutically acceptable excipients used in the manufacture ofprovided compositions include inert diluents, dispersing and/orgranulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as coloring agents,coating agents, perfuming agents, and sunscreens may also be present inthe composition.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, etc., and combinations thereof.

Exemplary surface active agents and/or emulsifiers includelipids/natural emulsifiers (e.g. acacia, agar, alginic acid, sodiumalginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin,egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidalclays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminumsilicate]), long chain amino acid derivatives, high molecular weightalcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylenesorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60],polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate[Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span65], glyceryl monooleate, sorbitan monooleate [Span 80]),polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45],polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and Solutol), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethyleneethers, (e.g. polyoxyethylene lauryl ether [Brij 30]),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, etc. and/or combinations thereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, etc., and/or combinations thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal. Chlorobutanol, for example, can beused as a preservative in an ointment formulation at a concentration of0.001% to 1% by weight (such as 0.5% per weight) of the total weight ofthe final composition.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, etc., and combinations thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, etc., and combinations thereof.

Exemplary oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary oils include, but are not limited to, butylstearate, caprylic triglyceride, capric triglyceride, cyclomethicone,diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil,octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

A composition of the invention can be combined with, incorporated into,and/or delivered by means of a patch or dressing, which often have theadded advantage of providing controlled delivery of the PFPRA compoundto the body. Alternatively or additionally, the rate can be controlledby either providing a rate controlling membrane and/or by dispersing thePFPRA compound in a polymer matrix and/or gel.

The composition may further comprise one or more of the additionalingredients described herein. In some embodiments, the additionalingredient is a sunscreen, moisturizer, colorant, antibiotic,antifungal, antiviral, antifibrotic, anti-inflammatory, anesthetic,analgesic, vasoconstrictor, vasodilator, vitamin or mineral, orantioxidant.

Although the descriptions of compositions provided herein areprincipally directed to compositions that are suitable for topicaladministration to humans, it will be understood by the skilled artisanthat such compositions are generally suitable for administration toanimals of all sorts. Modification of compositions suitable foradministration to humans in order to render the compositions suitablefor administration to various animals is well understood, and theordinarily skilled veterinary pharmacologist can design and/or performsuch modification with ordinary experimentation. General considerationsin the formulation and/or manufacture of compositions can be found, forexample, in Remington: The Science and Practice of Pharmacy 21st ed.,Lippincott Williams & Wilkins, 2005.

Still further encompassed by the invention are kits comprising acomposition of the invention as described herein and instructions foruse. Kits provided may comprise a provided composition and a container(e.g., a tube, vial, ampoule, bottle, syringe, and/or dispenser package,or other suitable container).

Methods of Treatment and Use

As generally described herein, the compositions described herein arecontemplated useful in the reduction of subcutaneous fat in a subject inneed thereof. Methods of use and treatment include therapeutic methodsand cosmetic methods, as described herein. For example, in one aspect,provided is a method of reducing body fat in a subject, comprisingtopically administering a composition as described herein to a subjectin need thereof. In another aspect, provided is a composition of thepresent invention for use in method of reducing body fat in a subject.In another aspect, provided use of a composition of the presentinvention in the manufacture of a medicament for reducing body fat in asubject. In certain embodiments, the method is a therapeutic method. Incertain embodiments, the method is a cosmetic method.

Fat reduction can include reducing fat as measured by at least one ofvolume, size, mass, bulk, density, amount, and/or quantity. The presentinvention is expected to reduce fat by greater than or equal to 75%,greater than or equal to 70%, greater than or equal to 60%, greater thanor equal to 50%, greater than or equal to 40%, greater than or equal to30%, greater than or equal to 25%, greater than or equal to 20%, greaterthan or equal to 15%, greater than or equal to 10%, or greater than orequal to 5%. For example, fat reduction can also include reducing fatcell amount (for example, fat cell number), reducing fat cell volume,reducing fat cell maturation, and/or dedifferentiating a fat cell.

In certain embodiments, the body fat is local, e.g., concentrated on theface, chin, neck, arms, abdomen, chest, breast, buttocks, hips, thighs,legs, and/or knees.

In certain embodiments, the subject suffers from or is likely to sufferfrom obesity, excess fat on the breast, excess fat on the chin,gynecomastia, drug-induced obesity, hypothyroidism,pseudohypoparathyroidism, hypothalamic obesity, polycystic ovariandisease, depression, binge eating, postpartum obesity, obesityassociated with smoking cessation, Prader-Willi syndrome, Bardet-Biedlsyndrome, Cohen syndrome, Down syndrome, Turner syndrome, growth hormonedeficiency, growth hormone resistance, leptin deficiency or resistance,Cushing syndrome, pseudo-Cushing syndrome, hypertrophy of dorsocervicalfat/dorsocervical fat hypertrophy (“buffalo hump”), moon facies, HIVlipodystrophy, orbital fat prolapse, age-related descent of abnormalfat, other acquired lipodystrophy, familial lipodystrophy, lipoma,lipomatosis, or Madelung disease. In certain embodiments, the subjectsuffers from or is likely to suffer from obesity, gynecomastia, HIVlipodystrophy, lipoma, steatoblepharon, excess eyelid fat, excessperiorbital fat, or excess fat on the chin. In certain embodiments, thesubject has a cosmetic condition.

In certain embodiments, the subject suffers from or is likely to sufferfrom excess submental fat. Thus, in one aspect, provided is acomposition for use in for reducing fat in a subject suffering fromexcess submental fat. In another aspect, provided is a method oftreating excess submental fat in a subject, comprising topicallyadministering (e.g., applying to the submental skin of the subject) acomposition as described herein to a subject in need thereof. In anotheraspect, provided is a composition as described herein for use in amethod of treating excess submental fat in a subject. In another aspect,provided is use a composition as described herein in the manufacture ofa medicament for treating excess submental fat in a subject.

In certain embodiments, the subject suffers from or is likely to sufferfrom steatoblepharon. Thus, in one aspect, provided is a composition foruse in for reducing fat in a subject suffering from steatoblepharon. Inanother aspect, provided is a method of treating steatoblepharon in asubject, comprising topically administering (e.g., applying to an eyelidof the subject) a composition as described herein to a subject in needthereof. In another aspect, provided is a composition as describedherein for use in a method of treating steatoblepharon in a subject. Inanother aspect, provided is use a composition as described herein in themanufacture of a medicament for treating steatoblepharon in a subject.

As described herein, the route of administering is topical. In certainembodiments, the administering is to a body part selected from the groupconsisting of the face, chin, submental region, jowls, cheeks,periorbital skin, neck, arms, abdomen, chest, breast, buttocks, hips,thighs, legs, and knees.

In certain embodiments, the subject has excess body fat as a side effectof medication (e.g., for example, cortisol and analogs, corticosteroids,megace, sulfonylureas, anti-retrovirals, antidepressants, monoamineoxidase inhibitors, selective serotonin reuptake inhibitors, oralcontraceptives, insulin or a form of insulin, risperidone, clozapine,and thiazolidinediones).

In certain embodiments, the subject has excess body fat due to changesin hormonal status (e.g., as a result of physiologic changes such aspregnancy or menopause).

In certain embodiments, the subject with excess body fat is undergoingor has recently undergone smoking cessation.

In certain embodiments, the subject has body fat of cosmeticsignificance, for example, due to age-related orbital fat prolapse,excess submental fat, or descent of the malar fat pads.

This aspect of invention may also be useful as an adjunct to any ofvarious kinds of surgery and/or non-invasive therapy, whether used inthe pre-operative, peri-operative, or post-operative period. Theinvention further contemplates uses preceding abdominal, thoracic,oncologic, endocrine, neurologic, transplant, and dermatologic surgery,whereby surgical exposure may be improved; preceding or followingorthopedic procedures, whereby surgical exposure as well aspost-operative recovery may be improved; and preceding cosmeticprocedures using lasers, another type of radiation, thermal therapy,cryotherapy, ultrasound, electrolysis, chemical treatment and the like,e.g., skin tightening, skin resurfacing, collagen remodeling, and thelike.

Process for Manufacturing a Sterile Ointment

For ophthalmic use, e.g., application on the eyelid for reduction ofsteatoblepharon, a sterile composition is preferred. Certain of theinventive formulations (e.g., a composition comprising latanoprost,isopropyl myristate, and petrolatum) are not compatible with all formsof sterilization. For example, the inventors found that gammairradiation caused degradation of latanoprost (Example 14). Petroleumjelly is incompatible with autoclave sterilization and poorly suited formicrofiltration.

The inventors sought a practicable alternative. Having discovered thatlatanoprost is exceptionally soluble in isopropyl myristate (Example 3),the inventors developed a manufacturing process (cf. Example 4)comprising the steps of: (1) dissolving the PFPRA (e.g., latanoprost)and optionally other components (e.g., chlorobutanol) in the fatty acidester (e.g., isopropyl myristate) to make a solution; (2)microfiltration of the solution (e.g., under aseptic conditions) to makea sterile filtrate; and (3) addition of the filtrate to sterilepetroleum jelly, which is optionally liquefied, e.g., by heating (e.g.,from about 40° C. to about 70° C., e.g., about 50 to about 60° C.); and(4) mixing to obtain a uniform mixture. Upon reading the Examples, theskilled artisan can appreciate several advantages to combining thelatanoprost and PFPRA compound prior to microfiltration, as opposed tofiltering these components separately: latanoprost is very viscous andpoorly suited to microfiltration; the volume of latanoprost is generallysmall and therefore prone to measurement error (i.e., imprecision) andlosses in the so-called “dead space” of the microfilter; and dilutingthe latanoprost in the isopropyl myristate promotes uniformity of thelatanoprost in the final composition. However, the skilled artisan willalso appreciate that the strategy of dissolving the latanoprost in theisopropyl myristate would not be practicable, except for thefortuitously good solubility found by the inventors (Example 3).Furthermore, a surprising and advantageous property of mixing theisopropyl myristate in the petroleum jelly is that it substantiallyreduces the viscosity of the mixture, as compared to that of the purepetroleum jelly. This not only facilitates mixing (thereby promotinguniformity of the mixture) but also renders the composition moreflowable and spreadable on the skin, i.e., the pharmaceuticalcomposition is easier to dispense from a container and apply to theskin.

Thus, in another aspect, provided is a process for manufacturing one ormore of the inventive compositions in a sterile fashion, whereby thecomposition is sterile, endotoxin-free, and ophthalmically compatible,and therefore suitable for use on the eyelid or near the eye. Forexample, in one embodiment, provided is a process for manufacturing asterile ointment, comprising dissolving a PFPRA compound (e.g.latanoprost or tafluprost) in a fatty acid ester (e.g., isopropylmyristate) to make a solution; microfiltration of the solution to make afiltrate; and combining the filtrate with an ointment base (e.g., ahydrocarbon base such as petroleum jelly). In certain embodiments, themethod further comprises dissolving a preservative (e.g., chlorobutanol)in the fatty acid ester (e.g., isopropyl myristate).

EXAMPLES

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatthese compositions may also consist essentially of, or consist of, therecited components. Further, it should be understood that the order ofsteps or order for performing certain actions are immaterial so long asthe invention remains operable. Moreover, two or more steps or actionsmay be conducted simultaneously. In light of the foregoing description,the specific non-limiting examples presented below are for illustrativepurposes and not intended to limit the scope of the invention in anyway.

Example 1

A composition for local reduction of subcutaneous fat was prepared asfollows:

TABLE 1 Ingredients Amount Latanoprost 100 mg Isopropyl myristate 5 gPropylene glycol 15 g White petroleum jelly 79.9 g

Neat latanoprost was added to a mixture of propylene glycol andisopropyl myristate. To the resulting mixture was added melted petroleumjelly. The mixture was stirred thoroughly and allowed to cool, yieldingabout 100 grams of an ointment with a final latanoprost concentration of0.1% (w/w). It was noted that the compared to pure petrolatum, themixture was more flowable, more spreadable, more easily mixed (i.e.,requiring less force to mix), and more easily dispensed from acontainer, e.g., a jar or compressible tube (i.e., requiring less forceand flowing in a more controlled manner).

Example 2

A composition for local reduction of subcutaneous fat was prepared asfollows:

TABLE 2 Ingredients Amount per 100 g of composition Latanoprost 0.3 gChlorobutanol, anhydrous 0.5 g Isopropyl myristate 5 g White petroleumjelly 94.2 g

Chlorobutanol was dissolved in isopropyl myristate, and to the resultingsolution neat latanoprost was added and dissolved. To the resultingsolution was added melted petroleum jelly. The mixture was stirredthoroughly and allowed to cool, yielding about 100 grams of an ointmentwith a final latanoprost concentration of 0.3% (w/w). Compositions wereprepared according to the above formula at various scales ranging fromabout 50 to about 1000 g. Furthermore, comparable formulationscomprising 0.1%, 0.15%, and 0.5% (w/w) were likewise prepared, with thedifference in latanoprost content balanced by the amount of petroleumjelly. On HPLC analysis, these compositions were found to be uniform andto have the correct potency.

Example 3

The solubility of latanoprost in a 10:1 solution of isopropyl myristateand chlorobutanol was assessed by a standard (USP) protocol at 25° C.The upper limit of solubility at this temperature was found to be about60 to about 85 mg/g. This high degree of solubility was surprising,because latanoprost is insoluble or poorly soluble in most solvents.Furthermore, this high degree of solubility was crucial for practicingthe aseptic process described in the next example.

Example 4

A sterile, ophthalmically compatible composition for local reduction offat was prepared as follows:

TABLE 3 Ingredients Amount Latanoprost 100 mg Chlorobutanol, anhydrous0.5 g Isopropyl myristate 5 g White petroleum jelly 94.4 g

The process was carried out aseptically. Chlorobutanol (CB) wasdissolved in isopropyl myristate (IM). To this solution latanoprost wasadded and readily dissolved. The resulting solution was filtered througha 0.2 micron filter to yield a filtrate, which was placed in a sterilevessel. To the vessel was added sterile, melted petroleum jelly. Themixture was stirred thoroughly, yielding about 100 grams of a uniformointment with a final latanoprost concentration of 0.1% (w/w). Onlaboratory analysis, the ointment was sterile and free of endotoxins. Acomparable ointment comprising 0.3% (w/w) was prepared, with theadditional latanoprost replacing a like amount of petroleum jelly. Theskilled artisan will appreciate that the above process requireslatanoprost solubility in the IM:CB solution of at least 18 or 55 mg/gfor the 0.1% and 0.3% products, respectively.

Example 5

Compositions were prepared according to Example 2 and stored in atight-sealed container at room temperature. The latanoprostconcentration, uniformity, and lack of impurities were verified by HighPerformance Liquid Chromatography (HPLC). The composition was stored andreanalyzed and tested on HPLC at regular intervals for 2 months. At eachinterval, organoleptic inspection showed physical stability of thecomposition, and HPLC shows a stable latanoprost concentration and alack of known degradants (e.g., latanoprost free acid, 15-ketolatanoprost). Thus, it was concluded that the composition demonstratesexcellent physical and chemical stability.

Example 6

Skin permeation studies were conducted with various formulations oflatanoprost, ex vivo, on fresh human skin. Fresh human skin was obtainedfrom live donors undergoing abdominoplasty and mounted on a standard(Franz-type) diffusion cell apparatus. All formulations contained 0.8%of latanoprost, expressed as weight of latanoprost per total weight ofthe composition. Each test article (8 mg) was uniformly applied to askin surface of 0.8 cm². All formulations were tested on skin from atleast two different donors. Treated skin was left open to the atmosphereto simulate clinical conditions. Receptor fluid flowed continuously over24 hours and was collected in fractions. The amount of drug (latanoprostfree acid) in these fractions was determined by High-Performance LiquidChromatography (HPLC) with ultraviolet detection. The following amountsof drug were recovered from receptor fluid over 24 hours:

TABLE 4 Vehicle Formulation Drug mass (ng, mean) PG 15%, IM 5%, WPJ 80%10,808 PG 15%, PS 5%, WPJ 80% 3795 PG 7.5%, LL 7.5%, PS 5%, WPJ 80% 3635PG 7.5%, PS 5%, WPJ 87.5% 2082 PG 15%, PS 15%, WPJ 70%, 1127 Ethanol70%, PG 30% 3930 Ethanol 75%, DGME 25% 1260 Ethanol 75%, LL 25% 890Ethanol 50%, LL 25%, DGME 25% 840 DMSO 99% Gel 5850 DGME = diethyleneglycol monomethyl ether, DMSO = dimethylsulfoxide, IM = isopropylmyristate, LL = lauryl lactate, PG = propylene glycol, PS = polysorbate80, WPJ = white petroleum jelly.

Thus, a formulation of latanoprost comprising isopropyl myristate in ahydrocarbon base provided substantially more dermal drug penetrationcompared to similar formulations lacking isopropyl myristate. Theformulation comprising isopropyl myristate also provided superior drugpenetration to a positive control, which is DMSO 99% Gel, and comparedto a range of other formulations comprising enhancers such as lauryllactate, polysorbate 80, and diethylene glycol monoethyl ether.

Example 7

Skin permeation studies were conducted with various formulations oflatanoprost, ex vivo, on fresh pig skin, according to methods asdescribed in the foregoing example. All formulations contained 0.25% oflatanoprost, expressed as weight of latanoprost per total weight of thecomposition. The following flux values for LFA were observed over 24hours:

TABLE 5 Vehicle Formulation LFA flux (ng/cm²/h) MO 15%, IM 5%, WPJ 80% 8IM 5%, WPJ 95% 18 MO 15%, WPJ 85% 6 IM 5%, MO 95% 2 IM = isopropylmyristate, MO = mineral oil, WPJ = white petroleum jelly.

Thus, a formulation of latanoprost comprising petroleum jelly andisopropyl myristate, but lacking mineral oil, provided superior deliveryof LFA to formulations of latanoprost comprising mineral oil withisopropyl myristate, petroleum jelly, or both.

Example 8

Compositions as described in Example 2, comprising latanoprost at afinal concentration of 0.1% or 0.5%, were tested in Gottingen minipigs(3 animals per dose concentration). All animals were treated once dailyfor 10 days, over 10% of body surface area on the dorsal skin. Animalswere monitored for skin condition, body weight, and safety. Serialplasma samples were taken to assess pharmacokinetics. Twenty-four hoursafter the last dose, animals were sacrificed. Skin and fat weredissected from the treatment area. Tissues were examined histologically.Tissue was also used to measure drug (LFA) concentrations insubcutaneous fat (mid-depth of tissue) by liquid chromatography/tandemmass spectrometry (LC/MS/MS). The product was well tolerated, with noadverse effects in any animal. LFA concentrations in subcutaneous fatand plasma on Day 10 are shown in Table 6.

TABLE 6 LFA in mid-depth fat Formulation Duration (μg/g) (trough level)0.10% latanoprost 5% IM, 0.5% 10 days 0.2 CB, 94.4% petroleum jelly0.50% latanoprost, 5% IM, 0.5% 10 days 1 CB, 94% petroleum jelly CB =chlorobutanol; IM = isopropyl myristate

Thus, the compositions were well tolerated and, following application toa thick-skinned mammal, delivered LFA locally to subcutaneous fat.

Example 9

Compositions as described in Example 2, comprising latanoprost at afinal concentration of 0.1% or 0.5%, were tested on the periocular skinof Gottingen minipigs (3 animals per dose concentration). All animalswere treated once daily for 10 days. Animals were monitored for skincondition, body weight, and safety. Twenty-four hours after the lastdose, animals were sacrificed. Skin and fat were dissected from thetreatment area. Some of this tissue was examined histologically. Theproduct was well tolerated, with no adverse effects in any animal.

Example 10

Formulations consisting of latanoprost (0.1% or 0.5%), chlorobutanol0.5%, isopropyl myristate 5%, and white petroleum jelly q.s. (all w/w)were tested in a standard rabbit ocular irritation test. Theformulations did not cause any adverse effects.

Example 9

A composition comprising isopropyl myristate 5%, propylene glycol 15%,and white petroleum jelly 80% (without active ingredient) was applied toskin on the volar forearms on healthy adult men and women (n=4). Theapplication area was 5 cm×5 cm. Application was once daily for 7consecutive days. Skin condition and participant experience were noteddaily, with results as follows:

TABLE 4 Participant Skin Condition Participant Experience 1 Normal(100%) Well-tolerated, aesthetically pleasing 2 Normal (100%)Well-tolerated, aesthetically pleasing 3 Normal (100%) Well-tolerated,aesthetically pleasing 4 Normal (100%) Well-tolerated, aestheticallypleasing

Thus, the above formulations were non-irritating and aestheticallypleasing when applied to human skin.

Example 10

Different compositions, comprising latanoprost, e.g., 0.1% w/w, aretested on obese mice. Mice approximately six weeks old, all with similarbaseline body mass, are randomized and prospectively treated as follows(n=5 animals per group):

TABLE 5 Group Compound Formulation (w/w) A Vehicle only White petroleumjelly 100% B Vehicle only IM 5%, CB 0.5%, white petroleum jelly q.s. CLatanoprost White petroleum jelly q.s. D Latanoprost IM 5% CB 0.5%,white petroleum jelly q.s.

The dose is 0.1 cc to the right flank, daily. Mice are fed ad libitumand weighed daily for about 28 days. On or about day 28, mice aresacrificed and samples of skin with subcutaneous fat are collected forhistologic examination. It is predicted that after about 28 days, micein Group D will show relatively less weight gain (or more weight loss)and relatively less adiposity compared to mice in any of Groups A, B, orC. Thus, it is predicted that in a mouse model of obesity, the foregoingresults show superior reduction of adiposity with a latanoprostformulation comprising petroleum jelly, chlorobutanol, and isopropylmyristate, as compared to a equimolar latanoprost formulation with avehicle consisting essentially of petroleum jelly.

Example 11

A composition consisting essentially of latanoprost 0.5%, isopropylmyristate 5%, chlorobutanol 0.5%, and white petroleum jelly 94% (allw/w) was administered to the dorsal skin (10% of body surface area) ofsix Gottingen minipigs, once daily for 13 weeks. An equal number ofanimals are treated with a placebo composition, consisting essentiallyof isopropyl myristate 5%, chlorobutanol 0.5%, and white petroleum jelly94.5%. (all w/w). Animals were observed for safety and tolerability. Thecompositions were well tolerated in all animals. After 13 weeks, animalswere sacrificed and dorsal skin, fat, and muscle were dissected en blocfrom a standardized portion of the treatment area. As compared toanimals treated with the placebo composition, there was gross atrophy,i.e., a thickness reduction of 30% to 70%, of subcutaneous fat inanimals treated with the latanoprost 0.5% article.

Example 12

From the study described in Example 11, a portion of the tissue is fixedin formalin, stained with hematoxylin and eosin, and examinedhistopathologically. Subcutaneous fat thickness is measuredsystematically, for example by measuring the thickness of fat from thedermis to the panniculus carnosus using image analysis software such asImageJ (National Institutes of Health). From another portion of thetissue, subcutaneous fat is dissected, washed, pulverized, andhomogenized, with the homogenate submitted for quantification oflatanoprost free acid concentration using liquid chromatography withtandem mass spectrometry (a method known in the art). It is predictedthat the composition containing latanoprost will be associated withreduced subcutaneous fat thickness, as compared to control. It isfurther predicted that the latanoprost composition will be associatedwith amounts of latanoprost free acid in subcutaneous fat that areconsidered therapeutically effective, with reference to other in vivoexperiments and in vitro assays. It is further predicted that thelatanoprost composition of this example will be associated with highertissue concentrations of latanoprost free acid and/or higher degrees ofsubcutaneous fat reduction compared to other formulations hithertodisclosed.

Example 13

The following experiment describes a randomized, placebo-controlled,double-blind trial in human subjects to test whether the safety andefficacy of a PFPRA compound composition for reduction of submental fat.The composition can be, for example, as described in Example 2, whereinthe PFPRA compound is latanoprost. Alternatively, the PFPRA compound canbe, for example, tafluprost.

Eligible subjects (for example, n=60) with excess submental fat areentered into a randomized double-blind study. Subjects are randomized in1:1 fashion to receive either the active composition (for example,comprising latanoprost 0.3%), or the corresponding inactive vehicle.Subjects are instructed to apply, once a day, a dose of 0.5 ml in a thinfilm the chin. Serial clinical assessments, photographs, and magneticresonance imaging (MRI) scans are performed prior to the first dose andthen at 13 weeks. Treatment continues for a total of 13 weeks. It iscontemplated that over time, for example after 13 weeks of treatment,the composition comprising latanoprost (or tafluprost) will beassociated with more reduction in the depth and/or volume of submentalfat, as measured by clinical assessment and/or MRI, as compared tovehicle alone.

Example 14

The following experiment describes a randomized, placebo-controlled,double-blind trial in human subjects to test whether the safety andefficacy of a PFPRA compound composition for reduction of periorbitalfat. The composition can be, for example, a sterile composition asdescribed in Example 4, wherein the PFPRA compound is latanoprost.Alternatively, the PFPRA compound can be, for example, tafluprost.

Eligible subjects (for example, n=60) with excess periorbital fat areentered into a randomized double-blind study. Subjects are randomized in1:1 fashion to receive either the active composition (for example,comprising latanoprost 0.1%), or the corresponding inactive vehicle.Subjects are instructed to apply, once a day, a dose of 0.1 ml in a thinfilm the periorbital skin. Serial clinical assessments and photographsare performed prior to the first dose and then at 6 and 12 weeks.Treatment continues for a total of 12 weeks. It is contemplated thatover time, for example after 12 weeks of treatment, the compositioncomprising latanoprost (or other active ingredient) will be associatedwith more reduction in the volume of periorbital fat, as measured byclinical assessment, as compared to vehicle alone.

Example 15

A latanoprost ointment was prepared according to Example 2 and subjectedto various doses of gamma radiation, as are commonly used forsterilization. A validated HPLC method was used to evaluate the ointmentfor latanoprost content and degradants. Significant degradation oflatanoprost was observed at all gamma radiation doses. Thus, it wasfound that gamma irradiation is not suitable for sterilizingcompositions comprising latanoprost.

Other Embodiments

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A method for reducing body fat in a subject, themethod comprising administering to the subject a composition comprisinglatanoprost, isopropyl myristate, and petroleum jelly.
 2. The method ofclaim 1, wherein the method locally reduces body fat in the subject. 3.The method of claim 1, wherein the method reduces subcutaneous fat inthe subject.
 4. The method of claim 1, wherein the composition consistsessentially of latanoprost, isopropyl myristate, and petroleum jelly. 5.The method of claim 1, wherein the latanoprost concentration is betweenabout 0.001% and about 1% w/w, inclusive.
 6. The method of claim 5,wherein the latanoprost concentration is between about 0.01% and about0.5% w/w, inclusive.
 7. The method of claim 1, wherein the isopropylmyristate concentration is between about 1% and about 20% w/w,inclusive.
 8. The method of claim 7, wherein the isopropyl myristateconcentration is between about 1% and about 10% w/w, inclusive.
 9. Themethod of claim 5, wherein the isopropyl myristate concentration isbetween about 1% and about 20% w/w, inclusive.
 10. The method of claim9, wherein the isopropyl myristate concentration is between about 1% andabout 10% w/w, inclusive.
 11. The method of claim 1, wherein thepetroleum jelly concentration is between about 70% and about 99% w/w,inclusive.
 12. The method of claim 5, wherein the petroleum jellyconcentration is between about 70% and about 99% w/w, inclusive.
 13. Themethod of claim 1, wherein the composition further comprises apreservative.
 14. The method of claim 13, wherein the preservative ischlorobutanol.
 15. The method of claim 1, wherein the composition issterile.
 16. The method of claim 1, wherein the latanoprostconcentration is between about 0.001% and 1% w/w, inclusive; theisopropyl myristate concentration is between about 1% and about 10% w/w,inclusive; and the petroleum jelly concentration is between about 70%and about 99% w/w, inclusive.
 17. The method of claim 1, wherein thestep of administering is performed about once a day.
 18. The method ofclaim 1, wherein the step of administering comprises administering thecomposition to the face, chin, neck, arms, abdomen, chest, breast,buttocks, hips, thighs, legs, and/or knees.
 19. The method of claim 1,wherein the step of administering comprises administering thecomposition to the eyelids.
 20. The method of claim 1, wherein the stepof administering comprises administering the composition to thesubmental region.
 21. The method of claim 1, wherein the latanoprostconcentration is between about 0.03% and about 0.1% w/w, inclusive. 22.The method of claim 21, wherein the composition consists essentially oflatanoprost, isopropyl myristate, and petroleum jelly.
 23. The method ofclaim 16, wherein the latanoprost concentration is between about 0.03%and about 0.1% w/w, inclusive.
 24. The method of claim 23, wherein thecomposition consists essentially of latanoprost, isopropyl myristate,and petroleum jelly.
 25. The method of claim 1, wherein the latanoprostconcentration is about 0.1% w/w.
 26. The method of claim 25, wherein thecomposition consists essentially of latanoprost, isopropyl myristate,and petroleum jelly.
 27. The method of claim 16, wherein the latanoprostconcentration is about 0.1% w/w.
 28. The method of claim 27, wherein thecomposition consists essentially of latanoprost, isopropyl myristate,and petroleum jelly.